Pancreatic cancer detection kit or device, and detection method

ABSTRACT

This invention provides a kit or a device for the detection of pancreatic cancer, comprising a nucleic acid(s) capable of specifically binding to a miRNA(s) in a sample from a subject, and a method for detecting pancreatic cancer, comprising measuring the miRNA(s) in vitro.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.15/314,859, filed Jun. 5, 2017 (now allowed), which is a National Stageof International Application No. PCT/JP2015/065696 filed May 29, 2015,which claims priority based on Japanese Patent Application No.2014-113523, filed May 30, 2014, and Japanese Patent Application No.2014-185730, filed Sep. 11, 2014; the contents of all of which areincorporated herein by reference on their entirety.

REFERENCE TO SEQUENCE LISTING SUBMITTED VIA EFS-WEB

This application includes a sequence listing submitted in PDF format.The PDF file contains a sequence listing entitled“2019-06-24_SequenceListing_1254-0585PUS2.pdf” which was filed as aseparate amendment of the specification filed on May 30, 2018 in thelast filed computer readable form of the parent application Ser. No.15/341,859, which was filed on Jun. 5, 2017. The sequence listingcontained in this PDF file is part of the specification and is herebyincorporated by reference herein in its entirety.

TECHNICAL FIELD

The present invention relates to a kit or a device for the detection ofpancreatic cancer, comprising a nucleic acid capable of specificallybinding to a particular miRNA, which is used for examining the presenceor absence of pancreatic cancer in a subject, and a method for detectingpancreatic cancer, comprising measuring an expression level of the miRNAusing the nucleic acid.

BACKGROUND ART

The pancreas serves as an exocrine gland that secretes pancreatic juiceas a digestive juice and sends the juice into the digestive tractthrough the pancreatic duct, while also functioning as an endocrinegland that secretes hormones such as insulin and glucagon into blood.

Since the pancreas is surrounded by many organs such as the stomach, theduodenum, the small intestine, the liver, and the gallbladder,pancreatic cancer is not only difficult to detect early but hasproperties such as a lack of subjective symptoms, very rapidprogression, and metastasis to other organs and thus has very poorprognosis as compared with other cancers. According to the 2011statistics of cancer type-specific mortality in Japan disclosed by theCenter for Cancer Control and Information Services, National CancerCenter (Tokyo, Japan), the number of pancreatic cancer deaths climbed to28,829 people, and 5-year relative survival rates by cancer type in 2003to 2005 were lowest in pancreatic cancer with 7.1% for males and 6.9%for females.

As described in Non-Patent Literature 1, the basic therapy of pancreaticcancer is practiced by surgery, systemic chemotherapy, radiotherapy, ora combination thereof depending on a stage of progression. Although 15to 20% pancreatic cancer patients undergo surgery for potential cure,the great majority of patients who do not undergo surgery are consideredto have local progression or metastasis. The median survival time isreportedly 8 to 12 months for locally advanced cancer and 3 to 6 monthsfor metastatic cancer, which are very poor as compared with othercancers.

The UICC (Unio Internationalis Contra Cancrum) stages of progression ofpancreatic cancer are defined in General Rules for the Study ofPancreatic Cancer, the 5th edition (edited by Japan Pancreas Society,KANEHARA & Co., LTD., 2013, p. 55) and classified into stages 0, IA, IB,IIA, IIB, III, IVa, and IVb according to the size of primary tumor,lymph node metastasis, distant metastasis, etc. Stages I to III occupyhalf or more of the number of 5-year survivals, and stages IVa and IVboccupy 70% or more of the progressed stages at the time of diagnosis.Also, pancreatic cancer differs in symptoms among sites of origin.Carcinoma of the head of the pancreas often manifests jaundice, whereascarcinoma of the tail of the pancreas has few symptoms. Therefore, thecarcinoma of the tail of the pancreas tends to result in delayeddiagnosis as compared with the carcinoma of the head of the pancreas.

As described in Non-Patent Literature 2, abdominal ultrasonography isvery useful as convenient and limitedly invasive examination inoutpatient settings or medical examination for the diagnosis ofpancreatic cancer. However, it is often difficult to visualizepancreatic cancer having a small tumor size or a lesion on thepancreatic tail side. In ordinary medical checkup, the prevalence ofpancreatic cancer found in pancreatic images by abdominalultrasonography is approximately 1%, and the detection rate ofpancreatic cancer is approximately 0.06% or lower. For example, CA19-9,Span-1, CA50, CA242, Dupan-2, TAG-72, and urinary fucose as carbohydrateantigens, and CEA, POA, and TPS as non-carbohydrate antigens are knownas tumor markers for the detection of pancreatic cancer. As for how touse these tumor markers, a subject is suspected of having a cancer whentheir concentrations in blood are higher or lower than predeterminedreference values. For example, as described in Non-Patent Literature 3,the reference value of CEA is set to 5 ng/mL, and the reference value ofCA19-9 is set to 37 U/mL. A subject is suspected of having a cancerincluding pancreatic cancer when their concentrations exhibit thesevalues or higher. However, the evaluation of tumor markers oftenexamines advanced pancreatic cancer and does not show abnormal valuesfor early pancreatic cancer in many cases. Even combinatorial use oftumor markers and abdominal ultrasonography in medical examinationresults in low rates of detection of pancreatic cancer. Theimplementation of such medical examinations for the detection ofpancreatic cancer is controversial from the viewpoint of costeffectiveness.

As shown in Patent Literatures 1 to 4, there are reports, albeit at aresearch stage, on the determination of pancreatic cancer using theexpression levels of microRNAs (miRNAs), or combinations of theexpression levels of miRNAs and the expression levels of additionalprotein markers in biological samples including blood.

-   Patent Literature 1 discloses a method for detecting pancreatic    cancer by combining hsa-miR-125a-3p with dozens of other miRNAs in    blood.-   Patent Literature 2 discloses a method for detecting pancreatic    cancer by combining a hsa-miR-204-3p precursor, a hsa-miR-423-5p    precursor, or a hsa-miR-328-5p precursor with several hundreds of    other miRNAs in blood or tissues.-   Patent Literature 3 discloses a method for detecting pancreatic    cancer by combining hsa-miR-575, hsa-miR-16-5p, or hsa-miR-24-3p    with several hundreds of other miRNAs in blood.-   Patent Literature 4 discloses a method for detecting pancreatic    cancer by combining hsa-miR-451a with dozens of other miRNAs in    blood or tissues.-   Patent Literature 5 discloses a method for detecting pancreatic    cancer by combining a hsa-miR-150-3p precursor or a hsa-miR-187-5p    precursor with several hundreds of other miRNAs in blood or tissues.-   Non-Patent Literature 4 discloses hsa-miR-423-5p, hsa-miR-1246,    hsa-miR-150-3p, hsa-miR-550a-5p, hsa-miR-371a-5p, hsa-miR-1469,    hsa-miR-575, hsa-miR-564, hsa-miR-125a-3p, hsa-miR-451a,    hsa-miR-1908-5p and the like in plasma as miRNAs that have    significant difference in their expression levels between pancreatic    cancer patients and healthy subjects.-   Non-Patent Literature 5 discloses miR-3188, miR-16-5p, and the like    in plasma as miRNAs that have significant difference in their    expression levels between pancreatic cancer patients and healthy    subjects.-   Non-Patent Literature 6 discloses miR-550a-5p, miR-1290, miR-24-3p,    miR-486-3p, miR-423-5p, miR-125a-3p, and the like in serum as miRNAs    that have significant difference in their expression levels between    pancreatic cancer patients and healthy subjects.-   Non-Patent Literature 7 discloses miR-602 in tissues as a miRNA that    have significant difference in its expression level between    pancreatic cancer patients and healthy subjects.

PRIOR ART LITERATURE Patent Literature

-   Patent Literature 1: JP Patent Publication (Kohyo) No. 2012-507300 A    (2012)-   Patent Literature 2: Published U.S. Patent Application No.    2010/0286232-   Patent Literature 3: International Publication No. WO 2013/107459-   Patent Literature 4: Published U.S. Patent Application No.    2013/0310276-   Patent Literature 5: Published U.S. Patent Application No.    2008/0306018

Non-Patent Literature

-   Non-Patent Literature 1: Tetsuya Mine, “Suizo (Pancreas), Journal of    the Japan Pancreas Society”, Japan Pancreas Society, 2007, Vol.    22, p. 10-13 Non-Patent Literature 2: Japan Pancreas Society, “2009    Scientific evidence based clinical practice guidelines for    pancreatic cancer” CQ1 diagnosis methods    http://www.suizou.org/PCMG2009/cq1/cq1-3.html-   Non-Patent Literature 3: Kiyoshi Kurokawa et al. ed., LAB DATA,    2013, p. 633, 636 (Igaku-Shoin Ltd., Tokyo, Japan)-   Non-Patent Literature 4: Ali S. et al, 2011, American Journal of    Translational Research, Vol. 3, (1), p. 28-47-   Non-Patent Literature 5: Ganepola G A. et al., 2014, World Journal    of Gastrointestinal Oncology., Vol. 6, (1), p. 22-33-   Non-Patent Literature 6: Li A. et al., 2013, Clinical Cancer    Research, Vol. 19, (13), p. 3600-3610-   Non-Patent Literature 7: Zhang J. et al., 2014, Oncology Reports,    Vol. 31, (3), p. 1157-1164

SUMMARY OF INVENTION Problem to be Solved by Invention

An object of the present invention is to find novel tumor markers forpancreatic cancer and to provide a method that can effectively detectpancreatic cancer using nucleic acids capable of specifically binding tothe markers. As described in Non-Patent Literature 2, for example,CA19-9, Span-1, CA50, CA242, Dupan-2, TAG-72, and urinary fucose ascarbohydrate antigens and CEA, POA, and TPS as non-carbohydrate antigensare known as tumor markers for the detection of pancreatic cancer. Thepancreatic cancer detection sensitivity of these tumor markers is 70 to80% for CA19-9, 70 to 80% for Span-1, 50 to 60% for Dupan-2, 30 to 60%for CEA, and 60% for CA50. In addition, their specificity is not muchhigh, and their false positive rates are as high as 20 to 30%.Therefore, there may be the possibility of false detection of othercancers and/or benign tumors and/or benign diseases of the pancreasand/or peripancreatic organs, etc. Particularly, the detectionsensitivity of early pancreatic cancer is generally low, and thepositive rate of CA19-9 is merely ½ (52%) for pancreatic cancer having atumor size of 2 cm or smaller. Therefore, these tumor markers are notuseful for the detection of early pancreatic cancer. Furthermore, thetumor markers based on carbohydrate antigens exhibit false negatives inLewis blood type negative cases, in which the subjects do not producethe antigens. Therefore, this examination is unsuitable for somesubjects.

As described below, there are reports, albeit at a research stage, onthe determination of pancreatic cancer using the expression levels ofmicroRNAs (miRNAs) in biological samples including blood, none of which,however, have yet been brought into practical use.

Patent Literature 1 describes a method for diagnosing various cancersincluding pancreatic cancer by combining hsa-miR-125a-3p with a largenumber (dozens) of other miRNAs in blood. This literature, however,neither describes specific detection performance thereof such asaccuracy, sensitivity, or specificity nor describes a specific methodfor diagnosing pancreatic cancer using blood.

Patent Literature 2 describes a method for detecting pancreatic cancerby combining a hsa-miR-204-3p precursor, a hsa-miR-423-5p precursor, ora hsa-miR-328-5p precursor with several hundreds of other miRNAs inblood or tissues. This literature, however, neither describes specificdetection performance thereof such as accuracy, sensitivity, orspecificity nor describes a specific method for diagnosing pancreaticcancer using blood.

The method described in Patent Literature 3 diagnoses pancreatic cancerby combining hsa-miR-575, hsa-miR-16-5p, or hsa-miR-24-3p with severalhundreds of other miRNAs and does not state that diagnosis can beconducted by combining several miRNAs.

Patent Literature 4 employs hsa-miR-451a in combination with dozens ormore of other miRNAs in pancreatic cancer tissues for the diagnosis ofpancreatic cancer. This literature, however, does not describe aspecific method for diagnosing pancreatic cancer using blood.

Patent Literature 5 employs a hsa-miR-150-3p precursor or ahsa-miR-187-5p precursor in combination with several hundreds or more ofother miRNAs in pancreatic cancer tissues for the diagnosis ofpancreatic cancer. This literature, however, neither describes specificdetection performance thereof such as accuracy, sensitivity, orspecificity nor describes a specific method for diagnosing pancreaticcancer using blood.

In Non-Patent Literature 4, examples of the miRNAs that have significantdifference in their expression levels in plasma between pancreaticcancer patients and healthy subjects include miR-423-5p, miR-1246,miR-150-3p, miR-550a-5p, miR-371a-5p, miR-1469, miR-575, miR-564,miR-125a-3p, miR-451a, and miR-1908-5p. This literature, however, doesnot describe specific detection performance thereof such as accuracy,sensitivity, or specificity.

In Non-Patent Literature 5, examples of the miRNAs that have significantdifference in their expression levels in plasma between pancreaticcancer patients and healthy subjects include miR-3188 and miR-16-5p.However, as a result of validation, these miRNAs were excluded from theanalytes due to their low reliability.

In Non-Patent Literature 6, examples of the miRNAs that have significantdifference in their expression levels in serum between pancreatic cancerpatients and healthy subjects include miR-550a-5p, miR-1290, miR-24-3p,miR-486-3p, miR-423-5p, and miR-125a-3p. This literature, however,neither describes the specific detection performance, such as accuracy,sensitivity, or specificity, of miR-550a-5p, miR-24-3p, miR-486-3p,miR-423-5p, and miR-125a-3p nor validated the detection performance ofmiR-1290 in an independent sample group.

In Non-Patent Literature 7, examples of the miRNA that have significantdifference in its expression level in pancreatic tissues betweenpancreatic cancer patients and healthy subjects include miR-602. Thisliterature, however, neither describes specific detection performancethereof such as accuracy, sensitivity, or specificity nor describes aspecific method for diagnosing pancreatic cancer using blood.

As mentioned above, the existing tumor markers exhibit low performancein the detection of pancreatic cancer, or neither performance nordetection methods are specifically shown as to the markers at a researchstage. Therefore, use of these markers might require carrying outneedless extra examination due to the false detection of healthysubjects as being pancreatic cancer patients, or might waste therapeuticopportunity because of overlooking pancreatic cancer patients. Inaddition, the measurement of dozens to several hundreds of miRNAsincreases examination costs and is therefore difficult to use inlarge-scale screening such as medical checkup. Furthermore, thecollection of pancreatic tissues for measuring the tumor markers ishighly invasive to patients and is not favorable. Hence, there is ademand for a highly accurate pancreatic cancer marker that is detectablefrom blood, which can be collected in less invasive manner, and iscapable of correctly determining a pancreatic cancer patient as apancreatic cancer patient and a healthy subject as a healthy subject.Particularly, a highly sensitive pancreatic cancer marker is desiredbecause tumor resection based on early detection is only radical curefor pancreatic cancer.

Means for Solution of Problem

The present inventors have conducted diligent studies to attain theobject and consequently completed the present invention by findingseveral genes usable as markers for the detection of pancreatic cancerfrom blood, which can be collected with limited invasiveness, andfinding that pancreatic cancer can be significantly detected by usingnucleic acids capable of specifically binding to any of these markers.

SUMMARY OF INVENTION

The present invention has the following features:

(1) A kit for the detection of pancreatic cancer, comprising a nucleicacid(s) capable of specifically binding to at least one or morepolynucleotides selected from the group consisting of the followingpancreatic cancer markers: miR-6893-5p, miR-6075, miR-6820-5p, miR-4294,miR-6729-5p, miR-4476, miR-6836-3p, miR-6765-3p, miR-6799-5p, miR-4530,miR-7641, miR-4454, miR-615-5p, miR-8073, miR-663a, miR-4634, miR-4450,miR-4792, miR-665, miR-7975, miR-7109-5p, miR-6789-5p, miR-4497,miR-6877-5p, miR-6880-5p, miR-7977, miR-4734, miR-6821-5p, miR-8089,miR-5585-3p, miR-6085, miR-6845-5p, miR-4651, miR-4433-3p, miR-1231,miR-4665-5p, miR-7114-5p, miR-1238-5p, miR-8069, miR-4732-5p,miR-619-5p, miR-3622a-5p, miR-1260a, miR-6741-5p, miR-6781-5p, miR-6125,miR-6805-5p, miR-6132, miR-6872-3p, miR-6875-5p, miR-1908-3p,miR-4433b-3p, miR-4736, miR-5100, miR-6724-5p, miR-7107-5p, miR-6726-5p,miR-3185, miR-4638-5p, miR-1273g-3p, miR-6778-5p, miR-328-5p,miR-3679-3p, miR-1228-3p, miR-6779-5p, miR-4723-5p, miR-6850-5p,miR-760, miR-7704, miR-8072, miR-4486, miR-1913, miR-4656, miR-1260b,miR-7106-5p, miR-6889-5p, miR-6780b-5p, miR-6090, miR-4534, miR-4449,miR-5195-3p, miR-1202, miR-4467, miR-6515-3p, miR-4281, miR-4505,miR-4484, miR-6805-3p, miR-3135b, miR-3162-5p, miR-6768-5p, miR-6721-5p,miR-1227-5p, miR-6722-3p, miR-4286, miR-4746-3p, miR-6727-5p,miR-6816-5p, miR-4741, miR-4508, miR-940, miR-4327, miR-4665-3p,miR-718, miR-1203, miR-663b, miR-4258, miR-4649-5p, miR-4516,miR-3619-3p, miR-6826-5p, miR-6757-5p, miR-3131, miR-1343-3p,miR-6775-5p, miR-6813-5p, and miR-3940-5p.

(2) The kit according to (1), wherein miR-6893-5p is hsa-miR-6893-5p,miR-6075 is hsa-miR-6075, miR-6820-5p is hsa-miR-6820-5p, miR-4294 ishsa-miR-4294, miR-6729-5p is hsa-miR-6729-5p, miR-4476 is hsa-miR-4476,miR-6836-3p is hsa-miR-6836-3p, miR-6765-3p is hsa-miR-6765-3p,miR-6799-5p is hsa-miR-6799-5p, miR-4530 is hsa-miR-4530, miR-7641 ishsa-miR-7641, miR-4454 is hsa-miR-4454, miR-615-5p is hsa-miR-615-5p,miR-8073 is hsa-miR-8073, miR-663a is hsa-miR-663a, miR-4634 ishsa-miR-4634, miR-4450 is hsa-miR-4450, miR-4792 is hsa-miR-4792,miR-665 is hsa-miR-665, miR-7975 is hsa-miR-7975, miR-7109-5p ishsa-miR-7109-5p, miR-6789-5p is hsa-miR-6789-5p, miR-4497 ishsa-miR-4497, miR-6877-5p is hsa-miR-6877-5p, miR-6880-5p ishsa-miR-6880-5p, miR-7977 is hsa-miR-7977, miR-4734 is hsa-miR-4734,miR-6821-5p is hsa-miR-6821-5p, miR-8089 is hsa-miR-8089, miR-5585-3p ishsa-miR-5585-3p, miR-6085 is hsa-miR-6085, miR-6845-5p ishsa-miR-6845-5p, miR-4651 is hsa-miR-4651, miR-4433-3p ishsa-miR-4433-3p, miR-1231 is hsa-miR-1231, miR-4665-5p ishsa-miR-4665-5p, miR-7114-5p is hsa-miR-7114-5p, miR-1238-5p ishsa-miR-1238-5p, miR-8069 is hsa-miR-8069, miR-4732-5p ishsa-miR-4732-5p, miR-619-5p is hsa-miR-619-5p, miR-3622a-5p ishsa-miR-3622a-5p, miR-1260a is hsa-miR-1260a, miR-6741-5p ishsa-miR-6741-5p, miR-6781-5p is hsa-miR-6781-5p, miR-6125 ishsa-miR-6125, miR-6805-5p is hsa-miR-6805-5p, miR-6132 is hsa-miR-6132,miR-6872-3p is hsa-miR-6872-3p, miR-6875-5p is hsa-miR-6875-5p,miR-1908-3p is hsa-miR-1908-3p, miR-4433b-3p is hsa-miR-4433b-3p,miR-4736 is hsa-miR-4736, miR-5100 is hsa-miR-5100, miR-6724-5p ishsa-miR-6724-5p, miR-7107-5p is hsa-miR-7107-5p, miR-6726-5p ishsa-miR-6726-5p, miR-3185 is hsa-miR-3185, miR-4638-5p ishsa-miR-4638-5p, miR-1273g-3p is hsa-miR-1273g-3p, miR-6778-5p ishsa-miR-6778-5p, miR-328-5p is hsa-miR-328-5p, miR-3679-3p ishsa-miR-3679-3p, miR-1228-3p is hsa-miR-1228-3p, miR-6779-5p ishsa-miR-6779-5p, miR-4723-5p is hsa-miR-4723-5p, miR-6850-5p ishsa-miR-6850-5p, miR-760 is hsa-miR-760, miR-7704 is hsa-miR-7704,miR-8072 is hsa-miR-8072, miR-4486 is hsa-miR-4486, miR-1913 ishsa-miR-1913, miR-4656 is hsa-miR-4656, miR-1260b is hsa-miR-1260b,miR-7106-5p is hsa-miR-7106-5p, miR-6889-5p is hsa-miR-6889-5p,miR-6780b-5p is hsa-miR-6780b-5p, miR-6090 is hsa-miR-6090, miR-4534 ishsa-miR-4534, miR-4449 is hsa-miR-4449, miR-5195-3p is hsa-miR-5195-3p,miR-1202 is hsa-miR-1202, miR-4467 is hsa-miR-4467, miR-6515-3p ishsa-miR-6515-3p, miR-4281 is hsa-miR-4281, miR-4505 is hsa-miR-4505,miR-4484 is hsa-miR-4484, miR-6805-3p is hsa-miR-6805-3p, miR-3135b ishsa-miR-3135b, miR-3162-5p is hsa-miR-3162-5p, miR-6768-5p ishsa-miR-6768-5p, miR-6721-5p is hsa-miR-6721-5p, miR-1227-5p ishsa-miR-1227-5p, miR-6722-3p is hsa-miR-6722-3p, miR-4286 ishsa-miR-4286, miR-4746-3p is hsa-miR-4746-3p, miR-6727-5p ishsa-miR-6727-5p, miR-6816-5p is hsa-miR-6816-5p, miR-4741 ishsa-miR-4741, miR-4508 is hsa-miR-4508, miR-940 is hsa-miR-940, miR-4327is hsa-miR-4327, miR-4665-3p is hsa-miR-4665-3p, miR-718 is hsa-miR-718,miR-1203 is hsa-miR-1203, miR-663b is hsa-miR-663b, miR-4258 ishsa-miR-4258, miR-4649-5p is hsa-miR-4649-5p, miR-4516 is hsa-miR-4516,miR-3619-3p is hsa-miR-3619-3p, miR-6826-5p is hsa-miR-6826-5p,miR-6757-5p is hsa-miR-6757-5p, miR-3131 is hsa-miR-3131, miR-1343-3p ishsa-miR-1343-3p, miR-6775-5p is hsa-miR-6775-5p, miR-6813-5p ishsa-miR-6813-5p, and miR-3940-5p is hsa-miR-3940-5p.

(3) The kit according to (1) or (2), wherein the nucleic acid(s) is apolynucleotide(s) selected from the group consisting of the followingpolynucleotides (a) to (e):

(a) a polynucleotide consisting of a nucleotide sequence represented byany of SEQ ID NOs: 1 to 104, 464 to 473, and 492 to 494 or a nucleotidesequence derived from the nucleotide sequence by the replacement of uwith t, a variant thereof, a derivative thereof, or a fragment thereofcomprising 15 or more consecutive nucleotides;(b) a polynucleotide comprising a nucleotide sequence represented by anyof SEQ ID NOs: 1 to 104, 464 to 473, and 492 to 494;(c) a polynucleotide consisting of a nucleotide sequence complementaryto a nucleotide sequence represented by any of SEQ ID NOs: 1 to 104, 464to 473, and 492 to 494 or a nucleotide sequence derived from thenucleotide sequence by the replacement of u with t, a variant thereof, aderivative thereof, or a fragment thereof comprising 15 or moreconsecutive nucleotides;(d) a polynucleotide comprising a nucleotide sequence complementary to anucleotide sequence represented by any of SEQ ID NOs: 1 to 104, 464 to473, and 492 to 494 or a nucleotide sequence derived from the nucleotidesequence by the replacement of u with t; and(e) a polynucleotide hybridizing under stringent conditions to any ofthe polynucleotides (a) to (d).

(4) The kit according to any of (1) to (3), further comprising, inaddition to the nucleic acid(s), a nucleic acid(s) capable ofspecifically binding to at least one or more polynucleotides selectedfrom the group consisting of miR-125a-3p, miR-204-3p, miR-1469, miR-575,miR-150-3p, miR-423-5p, miR-564, miR-3188, miR-1246, miR-602, miR-1290,miR-16-5p, miR-451a, miR-24-3p, miR-187-5p, miR-1908-5p, miR-371a-5p,and miR-550a-5p.

(5) The kit according to (4), wherein miR-125a-3p is hsa-miR-125a-3p,miR-204-3p is hsa-miR-204-3p, miR-1469 is hsa-miR-1469, miR-575 ishsa-miR-575, miR-150-3p is hsa-miR-150-3p, miR-423-5p is hsa-miR-423-5p,miR-564 is hsa-miR-564, miR-3188 is hsa-miR-3188, miR-1246 ishsa-miR-1246, miR-602 is hsa-miR-602, miR-1290 is hsa-miR-1290,miR-16-5p is hsa-miR-16-5p, miR-451a is hsa-miR-451a, miR-24-3p ishsa-miR-24-3p, miR-187-5p is hsa-miR-187-5p, miR-1908-5p ishsa-miR-1908-5p, miR-371a-5p is hsa-miR-371a-5p, and miR-550a-5p ishsa-miR-550a-5p.

(6) The kit according to (4) or (5), wherein the nucleic acid(s) furthercomprise a polynucleotide(s) selected from the group consisting of thefollowing polynucleotides (f) to (j):

(f) a polynucleotide consisting of a nucleotide sequence represented byany of SEQ ID NOs: 105 to 122 or a nucleotide sequence derived from thenucleotide sequence by the replacement of u with t, a variant thereof, aderivative thereof, or a fragment thereof comprising 15 or moreconsecutive nucleotides;(g) a polynucleotide comprising a nucleotide sequence represented by anyof SEQ ID NOs: 105 to 122;(h) a polynucleotide consisting of a nucleotide sequence complementaryto a nucleotide sequence represented by any of SEQ ID NOs: 105 to 122 ora nucleotide sequence derived from the nucleotide sequence by thereplacement of u with t, a variant thereof, a derivative thereof, or afragment thereof comprising 15 or more consecutive nucleotides;(i) a polynucleotide comprising a nucleotide sequence complementary to anucleotide sequence represented by any of SEQ ID NOs: 105 to 122 or anucleotide sequence derived from the nucleotide sequence by thereplacement of u with t; and(j) a polynucleotide hybridizing under stringent conditions to any ofthe polynucleotides (0 to (i).

(7) The kit according to any of (1) to (6), further comprising, inaddition to the nucleic acid(s), a nucleic acid(s) capable ofspecifically binding to at least one or more polynucleotides selectedfrom the group consisting of miR-4417, miR-4707-5p, miR-7847-3p,miR-2861, miR-4513, miR-7111-5p, miR-6777-5p, miR-7113-3p, miR-4648,miR-3184-5p, miR-4271, miR-6791-5p, miR-642a-3p, miR-7108-5p,miR-128-1-5p, miR-5196-5p, miR-3178, miR-3656, miR-92a-2-5p,miR-6769b-5p, miR-4689, miR-6076, miR-92b-5p, miR-6774-5p, miR-486-3p,miR-6806-5p, miR-6842-5p, miR-6716-5p, miR-557, miR-4673, miR-4674,miR-4442, miR-1915-3p, miR-4687-3p, and miR-92b-3p.

(8) The kit according to claim 7), wherein miR-4417 is hsa-miR-4417,miR-4707-5p is hsa-miR-4707-5p, miR-7847-3p is hsa-miR-7847-3p, miR-2861is hsa-miR-2861, miR-4513 is hsa-miR-4513, miR-7111-5p ishsa-miR-7111-5p, miR-6777-5p is hsa-miR-6777-5p, miR-7113-3p ishsa-miR-7113-3p, miR-4648 is hsa-miR-4648, miR-3184-5p ishsa-miR-3184-5p, miR-4271 is hsa-miR-4271, miR-6791-5p ishsa-miR-6791-5p, miR-642a-3p is hsa-miR-642a-3p, miR-7108-5p ishsa-miR-7108-5p, miR-128-1-5p is hsa-miR-128-1-5p, miR-5196-5p ishsa-miR-5196-5p, miR-3178 is hsa-miR-3178, miR-3656 is hsa-miR-3656,miR-92a-2-5p is hsa-miR-92a-2-5p, miR-6769b-5p is hsa-miR-6769b-5p,miR-4689 is hsa-miR-4689, miR-6076 is hsa-miR-6076, miR-92b-5p ishsa-miR-92b-5p, miR-6774-5p is hsa-miR-6774-5p, miR-486-3p ishsa-miR-486-3p, miR-6806-5p is hsa-miR-6806-5p, miR-6842-5p ishsa-miR-6842-5p, miR-6716-5p is hsa-miR-6716-5p, miR-557 is hsa-miR-557,miR-4673 is hsa-miR-4673, miR-4674 is hsa-miR-4674, miR-4442 ishsa-miR-4442, miR-1915-3p is hsa-miR-1915-3p, miR-4687-3p ishsa-miR-4687-3p, and miR-92b-3p is hsa-miR-92b-3p.

(9) The kit according to (7) or (8), wherein the nucleic acid(s) is apolynucleotide(s) selected from the group consisting of the followingpolynucleotides (k) to (o):

(k) a polynucleotide consisting of a nucleotide sequence represented byany of SEQ ID NOs: 349 to 383 or a nucleotide sequence derived from thenucleotide sequence by the replacement of u with t, a variant thereof, aderivative thereof, or a fragment thereof comprising 15 or moreconsecutive nucleotides;(l) a polynucleotide comprising a nucleotide sequence represented by anyof SEQ ID NOs: 349 to 383;(m) a polynucleotide consisting of a nucleotide sequence complementaryto a nucleotide sequence represented by any of SEQ ID NOs: 349 to 383 ora nucleotide sequence derived from the nucleotide sequence by thereplacement of u with t, a variant thereof, a derivative thereof, or afragment thereof comprising 15 or more consecutive nucleotides;(n) a polynucleotide comprising a nucleotide sequence complementary to anucleotide sequence represented by any of SEQ ID NOs: 349 to 383 or anucleotide sequence derived from the nucleotide sequence by thereplacement of u with t; and(o) a polynucleotide hybridizing under stringent conditions to any ofthe polynucleotides (k) to (n).

(10) The kit according to any one of (1) to (9), wherein the kitcomprises at least two or more nucleic acids capable of specificallybinding to at least two or more polynucleotides, respectively, selectedfrom all of the pancreatic cancer markers according to (1) or (2).

(11) A device for the detection of pancreatic cancer, comprising anucleic acid(s) capable of specifically binding to at least one or morepolynucleotides selected from the group consisting of pancreatic cancermarkers miR-6893-5p, miR-6075, miR-6820-5p, miR-4294, miR-6729-5p,miR-4476, miR-6836-3p, miR-6765-3p, miR-6799-5p, miR-4530, miR-7641,miR-4454, miR-615-5p, miR-8073, miR-663a, miR-4634, miR-4450, miR-4792,miR-665, miR-7975, miR-7109-5p, miR-6789-5p, miR-4497, miR-6877-5p,miR-6880-5p, miR-7977, miR-4734, miR-6821-5p, miR-8089, miR-5585-3p,miR-6085, miR-6845-5p, miR-4651, miR-4433-3p, miR-1231, miR-4665-5p,miR-7114-5p, miR-1238-5p, miR-8069, miR-4732-5p, miR-619-5p,miR-3622a-5p, miR-1260a, miR-6741-5p, miR-6781-5p, miR-6125,miR-6805-5p, miR-6132, miR-6872-3p, miR-6875-5p, miR-1908-3p,miR-4433b-3p, miR-4736, miR-5100, miR-6724-5p, miR-7107-5p, miR-6726-5p,miR-3185, miR-4638-5p, miR-1273g-3p, miR-6778-5p, miR-328-5p,miR-3679-3p, miR-1228-3p, miR-6779-5p, miR-4723-5p, miR-6850-5p,miR-760, miR-7704, miR-8072, miR-4486, miR-1913, miR-4656, miR-1260b,miR-7106-5p, miR-6889-5p, miR-6780b-5p, miR-6090, miR-4534, miR-4449,miR-5195-3p, miR-1202, miR-4467, miR-6515-3p, miR-4281, miR-4505,miR-4484, miR-6805-3p, miR-3135b, miR-3162-5p, miR-6768-5p, miR-6721-5p,miR-1227-5p, miR-6722-3p, miR-4286, miR-4746-3p, miR-6727-5p,miR-6816-5p, miR-4741, miR-4508, miR-940, miR-4327, miR-4665-3p,miR-718, miR-1203, miR-663b, miR-4258, miR-4649-5p, miR-4516,miR-3619-3p, miR-6826-5p, miR-6757-5p, miR-3131, miR-1343-3p,miR-6775-5p, miR-6813-5p, and miR-3940-5p.

(12) The device according to (11), wherein miR-6893-5p ishsa-miR-6893-5p, miR-6075 is hsa-miR-6075, miR-6820-5p ishsa-miR-6820-5p, miR-4294 is hsa-miR-4294, miR-6729-5p ishsa-miR-6729-5p, miR-4476 is hsa-miR-4476, miR-6836-3p ishsa-miR-6836-3p, miR-6765-3p is hsa-miR-6765-3p, miR-6799-5p ishsa-miR-6799-5p, miR-4530 is hsa-miR-4530, miR-7641 is hsa-miR-7641,miR-4454 is hsa-miR-4454, miR-615-5p is hsa-miR-615-5p, miR-8073 ishsa-miR-8073, miR-663a is hsa-miR-663a, miR-4634 is hsa-miR-4634,miR-4450 is hsa-miR-4450, miR-4792 is hsa-miR-4792, miR-665 ishsa-miR-665, miR-7975 is hsa-miR-7975, miR-7109-5p is hsa-miR-7109-5p,miR-6789-5p is hsa-miR-6789-5p, miR-4497 is hsa-miR-4497, miR-6877-5p ishsa-miR-6877-5p, miR-6880-5p is hsa-miR-6880-5p, miR-7977 ishsa-miR-7977, miR-4734 is hsa-miR-4734, miR-6821-5p is hsa-miR-6821-5p,miR-8089 is hsa-miR-8089, miR-5585-3p is hsa-miR-5585-3p, miR-6085 ishsa-miR-6085, miR-6845-5p is hsa-miR-6845-5p, miR-4651 is hsa-miR-4651,miR-4433-3p is hsa-miR-4433-3p, miR-1231 is hsa-miR-1231, miR-4665-5p ishsa-miR-4665-5p, miR-7114-5p is hsa-miR-7114-5p, miR-1238-5p ishsa-miR-1238-5p, miR-8069 is hsa-miR-8069, miR-4732-5p ishsa-miR-4732-5p, miR-619-5p is hsa-miR-619-5p, miR-3622a-5p ishsa-miR-3622a-5p, miR-1260a is hsa-miR-1260a, miR-6741-5p ishsa-miR-6741-5p, miR-6781-5p is hsa-miR-6781-5p, miR-6125 ishsa-miR-6125, miR-6805-5p is hsa-miR-6805-5p, miR-6132 is hsa-miR-6132,miR-6872-3p is hsa-miR-6872-3p, miR-6875-5p is hsa-miR-6875-5p,miR-1908-3p is hsa-miR-1908-3p, miR-4433b-3p is hsa-miR-4433b-3p,miR-4736 is hsa-miR-4736, miR-5100 is hsa-miR-5100, miR-6724-5p ishsa-miR-6724-5p, miR-7107-5p is hsa-miR-7107-5p, miR-6726-5p ishsa-miR-6726-5p, miR-3185 is hsa-miR-3185, miR-4638-5p ishsa-miR-4638-5p, miR-1273g-3p is hsa-miR-1273g-3p, miR-6778-5p ishsa-miR-6778-5p, miR-328-5p is hsa-miR-328-5p, miR-3679-3p ishsa-miR-3679-3p, miR-1228-3p is hsa-miR-1228-3p, miR-6779-5p ishsa-miR-6779-5p, miR-4723-5p is hsa-miR-4723-5p, miR-6850-5p ishsa-miR-6850-5p, miR-760 is hsa-miR-760, miR-7704 is hsa-miR-7704,miR-8072 is hsa-miR-8072, miR-4486 is hsa-miR-4486, miR-1913 ishsa-miR-1913, miR-4656 is hsa-miR-4656, miR-1260b is hsa-miR-1260b,miR-7106-5p is hsa-miR-7106-5p, miR-6889-5p is hsa-miR-6889-5p,miR-6780b-5p is hsa-miR-6780b-5p, miR-6090 is hsa-miR-6090, miR-4534 ishsa-miR-4534, miR-4449 is hsa-miR-4449, miR-5195-3p is hsa-miR-5195-3p,miR-1202 is hsa-miR-1202, miR-4467 is hsa-miR-4467, miR-6515-3p ishsa-miR-6515-3p, miR-4281 is hsa-miR-4281, miR-4505 is hsa-miR-4505,miR-4484 is hsa-miR-4484, miR-6805-3p is hsa-miR-6805-3p, miR-3135b ishsa-miR-3135b, miR-3162-5p is hsa-miR-3162-5p, miR-6768-5p ishsa-miR-6768-5p, miR-6721-5p is hsa-miR-6721-5p, miR-1227-5p ishsa-miR-1227-5p, miR-6722-3p is hsa-miR-6722-3p, miR-4286 ishsa-miR-4286, miR-4746-3p is hsa-miR-4746-3p, miR-6727-5p ishsa-miR-6727-5p, miR-6816-5p is hsa-miR-6816-5p, miR-4741 ishsa-miR-4741, miR-4508 is hsa-miR-4508, miR-940 is hsa-miR-940, miR-4327is hsa-miR-4327, miR-4665-3p is hsa-miR-4665-3p, miR-718 is hsa-miR-718,miR-1203 is hsa-miR-1203, miR-663b is hsa-miR-663b, miR-4258 ishsa-miR-4258, miR-4649-5p is hsa-miR-4649-5p, miR-4516 is hsa-miR-4516,miR-3619-3p is hsa-miR-3619-3p, miR-6826-5p is hsa-miR-6826-5p,miR-6757-5p is hsa-miR-6757-5p, miR-3131 is hsa-miR-3131, miR-1343-3p ishsa-miR-1343-3p, miR-6775-5p is hsa-miR-6775-5p, miR-6813-5p ishsa-miR-6813-5p, and miR-3940-5p is hsa-miR-3940-5p.

(13) The device according to (11) or (12), wherein the nucleic acid(s)is a polynucleotide(s) selected from the group consisting of thefollowing polynucleotides (a) to (e):

(a) a polynucleotide consisting of a nucleotide sequence represented byany of SEQ ID NOs: 1 to 104, 464 to 473, and 492 to 494 or a nucleotidesequence derived from the nucleotide sequence by the replacement of uwith t, a variant thereof, a derivative thereof, or a fragment thereofcomprising 15 or more consecutive nucleotides;(b) a polynucleotide comprising a nucleotide sequence represented by anyof SEQ ID NOs: 1 to 104, 464 to 473, and 492 to 494;(c) a polynucleotide consisting of a nucleotide sequence complementaryto a nucleotide sequence represented by any of SEQ ID NOs: 1 to 104, 464to 473, and 492 to 494 or a nucleotide sequence derived from thenucleotide sequence by the replacement of u with t, a variant thereof, aderivative thereof, or a fragment thereof comprising 15 or moreconsecutive nucleotides;(d) a polynucleotide comprising a nucleotide sequence complementary to anucleotide sequence represented by any of SEQ ID NOs: 1 to 104, 464 to473, and 492 to 494 or a nucleotide sequence derived from the nucleotidesequence by the replacement of u with t; and(e) a polynucleotide hybridizing under stringent conditions to any ofthe polynucleotides (a) to (d).

(14) The device according to any one of (11) to (13), wherein the devicefurther comprises a nucleic acid(s) capable of specifically binding toat least one or more polynucleotides selected from the group consistingof other pancreatic cancer markers miR-125a-3p, miR-204-3p, miR-1469,miR-575, miR-150-3p, miR-423-5p, miR-564, miR-3188, miR-1246, miR-602,miR-1290, miR-16-5p, miR-451a, miR-24-3p, miR-187-5p, miR-1908-5p,miR-371a-5p, and miR-550a-5p.

(15) The device according to (14), wherein miR-125a-3p ishsa-miR-125a-3p, miR-204-3p is hsa-miR-204-3p, miR-1469 is hsa-miR-1469,miR-575 is hsa-miR-575, miR-150-3p is hsa-miR-150-3p, miR-423-5p ishsa-miR-423-5p, miR-564 is hsa-miR-564, miR-3188 is hsa-miR-3188,miR-1246 is hsa-miR-1246, miR-602 is hsa-miR-602, miR-1290 ishsa-miR-1290, miR-16-5p is hsa-miR-16-5p, miR-451a is hsa-miR-451a,miR-24-3p is hsa-miR-24-3p, miR-187-5p is hsa-miR-187-5p, miR-1908-5p ishsa-miR-1908-5p, miR-371a-5p is hsa-miR-371a-5p, and miR-550a-5p ishsa-miR-550a-5p.

(16) The device according to (14) or (15), wherein the nucleic acid(s)is a polynucleotide(s) selected from the group consisting of thefollowing polynucleotides (0 to (j):

(f) a polynucleotide consisting of a nucleotide sequence represented byany of SEQ ID NOs: 105 to 122 or a nucleotide sequence derived from thenucleotide sequence by the replacement of u with t, a variant thereof, aderivative thereof, or a fragment thereof comprising 15 or moreconsecutive nucleotides;(g) a polynucleotide comprising a nucleotide sequence represented by anyof SEQ ID NOs: 105 to 122;(h) a polynucleotide consisting of a nucleotide sequence complementaryto a nucleotide sequence represented by any of SEQ ID NOs: 105 to 122 ora nucleotide sequence derived from the nucleotide sequence by thereplacement of u with t, a variant thereof, a derivative thereof, or afragment thereof comprising 15 or more consecutive nucleotides;(i) a polynucleotide comprising a nucleotide sequence complementary to anucleotide sequence represented by any of SEQ ID NOs: 105 to 122 or anucleotide sequence derived from the nucleotide sequence by thereplacement of u with t; and(j) a polynucleotide hybridizing under stringent conditions to any ofthe polynucleotides (0 to (i).

(17) The device according to any one of (11) to (16), wherein the devicefurther comprises a nucleic acid(s) capable of specifically binding toat least one or more polynucleotides selected from the group consistingof other pancreatic cancer markers miR-4417, miR-4707-5p, miR-7847-3p,miR-2861, miR-4513, miR-7111-5p, miR-6777-5p, miR-7113-3p, miR-4648,miR-3184-5p, miR-4271, miR-6791-5p, miR-642a-3p, miR-7108-5p,miR-128-1-5p, miR-5196-5p, miR-3178, miR-3656, miR-92a-2-5p,miR-6769b-5p, miR-4689, miR-6076, miR-92b-5p, miR-6774-5p, miR-486-3p,miR-6806-5p, miR-6842-5p, miR-6716-5p, miR-557, miR-4673, miR-4674,miR-4442, miR-1915-3p, miR-4687-3p and miR-92b-3p.

(18) The device according to (17), wherein miR-4417 is hsa-miR-4417,miR-4707-5p is hsa-miR-4707-5p, miR-7847-3p is hsa-miR-7847-3p, miR-2861is hsa-miR-2861, miR-4513 is hsa-miR-4513, miR-7111-5p ishsa-miR-7111-5p, miR-6777-5p is hsa-miR-6777-5p, miR-7113-3p ishsa-miR-7113-3p, miR-4648 is hsa-miR-4648, miR-3184-5p ishsa-miR-3184-5p, miR-4271 is hsa-miR-4271, miR-6791-5p ishsa-miR-6791-5p, miR-642a-3p is hsa-miR-642a-3p, miR-7108-5p ishsa-miR-7108-5p, miR-128-1-5p is hsa-miR-128-1-5p, miR-5196-5p ishsa-miR-5196-5p, miR-3178 is hsa-miR-3178, miR-3656 is hsa-miR-3656,miR-92a-2-5p is hsa-miR-92a-2-5p, miR-6769b-5p is hsa-miR-6769b-5p,miR-4689 is hsa-miR-4689, miR-6076 is hsa-miR-6076, miR-92b-5p ishsa-miR-92b-5p, miR-6774-5p is hsa-miR-6774-5p, miR-486-3p ishsa-miR-486-3p, miR-6806-5p is hsa-miR-6806-5p, miR-6842-5p ishsa-miR-6842-5p, miR-6716-5p is hsa-miR-6716-5p, miR-557 is hsa-miR-557,miR-4673 is hsa-miR-4673, miR-4674 is hsa-miR-4674, miR-4442 ishsa-miR-4442, miR-1915-3p is hsa-miR-1915-3p, miR-4687-3p ishsa-miR-4687-3p, and miR-92b-3p is hsa-miR-92b-3p.

(19) The device according to (17) or (18), wherein the nucleic acid(s)is a polynucleotide(s) selected from the group consisting of thefollowing polynucleotides (k) to (o):

(k) a polynucleotide consisting of a nucleotide sequence represented byany of SEQ ID NOs: 349 to 383 or a nucleotide sequence derived from thenucleotide sequence by the replacement of u with t, a variant thereof, aderivative thereof, or a fragment thereof comprising 15 or moreconsecutive nucleotides;(l) a polynucleotide comprising a nucleotide sequence represented by anyof SEQ ID NOs: 349 to 383;(m) a polynucleotide consisting of a nucleotide sequence complementaryto a nucleotide sequence represented by any of SEQ ID NOs: 349 to 383 ora nucleotide sequence derived from the nucleotide sequence by thereplacement of u with t, a variant thereof, a derivative thereof, or afragment thereof comprising 15 or more consecutive nucleotides;(n) a polynucleotide comprising a nucleotide sequence complementary to anucleotide sequence represented by any of SEQ ID NOs: 349 to 383 or anucleotide sequence derived from the nucleotide sequence by thereplacement of u with t; and(o) a polynucleotide hybridizing under stringent conditions to any ofthe polynucleotides (k) to (n).

(20) The device according to any one of (11) to (19), wherein the deviceis for measurement based on a hybridization technique.

(21) The device according to (20), wherein the hybridization techniqueis a nucleic acid array technique.

(22) The device according to any one of (11) to (21), wherein the devicecomprises at least two or more nucleic acids capable of specificallybinding to at least two or more polynucleotides, respectively, selectedfrom all of the pancreatic cancer markers according to (11) or (12).

(23) A method for detecting pancreatic cancer, comprising: measuring anexpression level(s) of a target nucleic acid(s) in a sample from asubject using a kit according to any one of (1) to (10) or a deviceaccording to any one of (11) to (22); and evaluating in vitro whether ornot the subject has pancreatic cancer using both of the measuredexpression level(s) and a control expression level(s) in a sample from ahealthy subject measured in the same way.

(24) The method according to (23), wherein the subject is a human.

(25) The method according to (23) or (24), wherein the sample is blood,serum, or plasma.

Definition of Terms

The terms used herein are defined as described below.

The term “pancreatic cancer” used herein refers to any malignant tumorformed in the pancreas. Specifically, the “pancreatic cancer” includesserous cystadenoma, mucinous cystadenocarcinoma, intraductalpapillary-mucinous carcinoma, invasive ductal carcinoma, acinar cellcarcinoma, neuroendocrine cancer, and the like (“General Rules for theStudy of Pancreatic Cancer”, the 6th edition, revised version, 2013,Japan Pancreas Society, KANEHARA & Co., LTD., p. 21-22).

The term “benign tumors and/or benign diseases of the pancreas and/orperipancreatic organs” used herein refers to diseases with nonmalignanttumors in the pancreas, the liver, and the bile duct.

Abbreviations or terms such as “nucleotide”, “polynucleotide”, “DNA”,and “RNA” used herein abide by “Guidelines for the preparation ofspecification which contain nucleotide and/or amino acid sequences”(edited by Japan Patent Office) and common use in the art.

The term “polynucleotide” used herein refers to a nucleic acid includingany of RNA, DNA, and RNA/DNA (chimera). The DNA includes any of cDNA,genomic DNA, and synthetic DNA. The RNA includes any of total RNA, mRNA,rRNA, miRNA, siRNA, snoRNA, snRNA, non-coding RNA and synthetic RNA.Here the “synthetic DNA” and the “synthetic RNA” refer to a DNA and anRNA artificially prepared using, for example, an automatic nucleic acidsynthesizer, on the basis of predetermined nucleotide sequences (whichmay be any of natural and non-natural sequences). The “non-naturalsequence” is intended to be used in a broad sense and includes, forexample, a sequence comprising substitution, deletion, insertion, and/oraddition of one or more nucleotides (i.e., a variant sequence) and asequence comprising one or more modified nucleotides (i.e., a modifiedsequence), which are different from the natural sequence. Herein, theterm “polynucleotide” is used interchangeably with the term “nucleicacid.”

The term “fragment” used herein is a polynucleotide having a nucleotidesequence that consists of a consecutive portion of a polynucleotide anddesirably has a length of 15 or more nucleotides, preferably 17 or morenucleotides, more preferably 19 or more nucleotides.

The term “gene” used herein is intended to include not only RNA anddouble-stranded DNA but also each single-stranded DNA such as a plus(+)strand (or a sense strand) or a complementary strand (or an antisensestrand) constituting the duplex. The gene is not particularly limited byits length.

Thus, the “gene” used herein includes any of double-stranded DNAincluding human genomic DNA, single-stranded DNA (plus strand),single-stranded DNA having a sequence complementary to the plus strand(complementary strand) including cDNA, microRNA (miRNA), and theirfragments, and their transcripts, unless otherwise specified. The “gene”includes not only a “gene” represented by a particular nucleotidesequence (or SEQ ID NO) but “nucleic acids” encoding RNAs havingbiological functions equivalent to RNA encoded by the gene, for example,a congener (i.e., a homolog or an ortholog), a variant (e.g., a geneticpolymorph), and a derivative. Specific examples of such a “nucleic acid”encoding a congener, a variant, or a derivative can include a “nucleicacid” having a nucleotide sequence hybridizing under stringentconditions described later to a complementary sequence of a nucleotidesequence represented by any of SEQ ID NOs: 1 to 499 or a nucleotidesequence derived from the nucleotide sequence by the replacement of uwith t. Regardless whether or not there is a difference in functionalregion, the “gene” can comprise, for example, expression controlregions, coding region, exons, or introns. The “gene” may be containedin a cell or may exist alone after being released from a cell.Alternatively, the “gene” may be in a state enclosed in a vesicle calledexosome.

The term “exosome” used herein is a vesicle that is encapsulated bylipid bilayer and secreted from a cell. The exosome is derived from amultivesicular endosome and may incorporate biomaterials such as “genes”(e.g., RNA or DNA) or proteins when released into an extracellularenvironment. The exosome is known to be contained in a body fluid suchas blood, serum, plasma, or lymph.

The term “transcript” used herein refers to an RNA synthesized from theDNA sequence of a gene as a template. RNA polymerase binds to a sitecalled promoter located upstream of the gene and adds ribonucleotidescomplementary to the nucleotide sequence of the DNA to the 3′ end tosynthesize an RNA. This RNA contains not only the gene itself but thewhole sequence from a transcription initiation site to the end of apolyA sequence, including expression control regions, coding region,exons, or introns.

Unless otherwise specified, the term “microRNA (miRNA)” used herein isintended to mean a 15- to 25-nucleotide non-coding RNA that istranscribed as an RNA precursor having a hairpin-like structure, cleavedby a dsRNA-cleaving enzyme having RNase III cleavage activity, andintegrated into a protein complex called RISC, and that is involved inthe suppression of translation of mRNA. The term “miRNA” used hereinincludes not only a “miRNA” represented by a particular nucleotidesequence (or SEQ ID NO) but a precursor of the “miRNA” (pre-miRNA orpri-miRNA), and miRNAs having biological functions equivalent thereto,for example, a congener (i.e., a homolog or an ortholog), a variant(e.g., a genetic polymorph), and a derivative. Such a precursor, acongener, a variant, or a derivative can be specifically identifiedusing miRBase Release 20 (http://www.mirbase.org/), and examples thereofcan include a “miRNA” having a nucleotide sequence hybridizing understringent conditions described later to a complementary sequence of anyparticular nucleotide sequence represented by any of SEQ ID NOs: 1 to499. The term “miRNA” used herein may be a gene product of a miR gene.Such a gene product includes a mature miRNA (e.g., a 15- to25-nucleotide or 19- to 25-nucleotide non-coding RNA involved in thesuppression of translation of mRNA as described above) or a miRNAprecursor (e.g., pre-miRNA or pri-miRNA as described above).

The term “probe” used herein includes a polynucleotide that is used forspecifically detecting an RNA resulting from the expression of a gene ora polynucleotide derived from the RNA, and/or a polynucleotidecomplementary thereto.

The term “primer” used herein includes a polynucleotide thatspecifically recognizes and amplifies an RNA resulting from theexpression of a gene or a polynucleotide derived from the RNA, and/or apolynucleotide complementary thereto.

In this context, the complementary polynucleotide (complementary strandor reverse strand) means a polynucleotide in a complementaryrelationship based on A:T (U) and G:C base pairs with the full-lengthsequence of a polynucleotide consisting of a nucleotide sequence definedby any of SEQ ID NOs: 1 to 499 or a nucleotide sequence derived from thenucleotide sequence by the replacement of u with t, or a partialsequence thereof (here, this full-length or partial sequence is referredto as a plus strand for the sake of convenience). However, such acomplementary strand is not limited to a sequence completelycomplementary to the nucleotide sequence of the target plus strand andmay have a complementary relationship to an extent that permitshybridization under stringent conditions to the target plus strand.

The term “stringent conditions” used herein refers to conditions underwhich a nucleic acid probe hybridizes to its target sequence to adetectably larger extent (e.g., a measurement value equal to or largerthan “(a mean of background measurement values)+(a standard deviation ofthe background measurement values)×2”) than that for other sequences.The stringent conditions are dependent on a sequence and differdepending on an environment where hybridization is performed. A targetsequence complementary 100% to the nucleic acid probe can be identifiedby controlling the stringency of hybridization and/or washingconditions. Specific examples of the “stringent conditions” will bementioned later.

The term “Tm value” used herein means a temperature at which thedouble-stranded moiety of a polynucleotide is denatured into singlestrands so that the double strands and the single strands exist at aratio of 1:1.

The term “variant” used herein means, in the case of a nucleic acid, anatural variant attributed to polymorphism, mutation, or the like; avariant containing the deletion, substitution, addition, or insertion of1 or 2 or more nucleotides in a nucleotide sequence represented by anyof SEQ ID NOs: 1 to 499 or a nucleotide sequence derived from thenucleotide sequence by the replacement of u with t, or a partialsequence thereof, a variant that exhibits percent (%) identity ofapproximately 90% or higher, approximately 95% or higher, approximately97% or higher, approximately 98% or higher, approximately 99% or higherto each of these nucleotide sequences or the partial sequences thereof;or a nucleic acid hybridizing under the stringent conditions definedabove to a polynucleotide or an oligonucleotide comprising each of thesenucleotide sequences or the partial sequences thereof.

The term “several” used herein means an integer of approximately 10, 9,8, 7, 6, 5, 4, 3, or 2.

The variant as usen herein can be prepared by use of a well-knowntechnique such as site-directed mutagenesis or mutagenesis using PCR.

The term “percent (%) identity” used herein can be determined with orwithout an introduced gap, using a protein or gene search system basedon BLAST or FASTA (Zheng Zhang et al., 2000, J. Comput. Biol., Vol. 7,p. 203-214; Altschul, S. F. et al., 1990, Journal of Molecular Biology,Vol. 215, p. 403-410; and Pearson, W. R. et al., 1988, Proc. Natl. Acad.Sci. U.S.A, Vol. 85, p. 2444-2448).

The term “derivative” used herein is meant to include unlimitedly amodified nucleic acid, for example, a derivative labeled with afluorophore or the like, a derivative containing a modified nucleotide(e.g., a nucleotide containing a group such as halogen, alkyl such asmethyl, alkoxy such as methoxy, thio, or carboxymethyl, and a nucleotidethat has undergone base rearrangement, double bond saturation,deamination, replacement of an oxygen molecule with a sulfur atom,etc.), PNA (peptide nucleic acid; Nielsen, P. E. et al., 1991, Science,Vol. 254, p. 1497-500), and LNA (locked nucleic acid; Obika, S. et al.,1998, Tetrahedron Lett., Vol. 39, p. 5401-5404).

As used herein, the “nucleic acid” capable of specifically binding to apolynucleotide selected from the pancreatic cancer marker miRNAsdescribed above is a synthesized or prepared nucleic acid andspecifically includes a “nucleic acid probe” or a “primer”. The “nucleicacid” is utilized directly or indirectly for detecting the presence orabsence of pancreatic cancer in a subject, for diagnosing the presenceor absence or the severity of pancreatic cancer, the presence or absenceor the degree of amelioration of pancreatic cancer, or the therapeuticsensitivity of pancreatic cancer, or for screening for a candidatesubstance useful in the prevention, amelioration, or treatment ofpancreatic cancer. The “nucleic acid” includes a nucleotide, anoligonucleotide, and a polynucleotide capable of specificallyrecognizing and binding to a transcript represented by any of SEQ IDNOs: 1 to 499 or a synthetic cDNA nucleic acid thereof in vivo,particularly, in a sample such as a body fluid (e.g., blood or urine),in relation to the development of pancreatic cancer. The nucleotide, theoligonucleotide, and the polynucleotide can be effectively used asprobes for detecting the aforementioned gene expressed in vivo, intissues, in cells, or the like on the basis of the properties describedabove, or as primers for amplifying the aforementioned gene expressed invivo.

The term “detection” used herein is interchangeable with the term“examination”, “measurement”, “detection”, or “decision support”. Asused herein, the term “evaluation” is meant to include diagnosing orevaluation-supporting on the basis of examination results or measurementresults.

The term “subject” used herein means a mammal such as a primateincluding a human and a chimpanzee, a pet animal including a dog and acat, a livestock animal including cattle, a horse, sheep, and a goat,and a rodent including a mouse and a rat. The term “healthy subject”also means such a mammal without the cancer to be detected.

The term “P” or “P value” used herein refers to a probability at which amore extreme statistic than that actually calculated from data undernull hypothesis is observed in a statistical test. Thus, smaller “P” or“P value” is regarded as being a more significant difference betweensubjects to be compared.

The term “sensitivity” used herein means a value of (the number of truepositives)/(the number of true positives+the number of false negatives).High sensitivity allows pancreatic cancer to be detected early, leadingto the complete resection of cancer sites and reduction in the rate ofrecurrence.

The term “specificity” used herein means a value of (the number of truenegatives)/(the number of true negatives+the number of false positives).High specificity prevents needless extra examination for healthysubjects misjudged as being pancreatic cancer patients, leading toreduction in burden on patients and reduction in medical expense.

The term “accuracy” used herein means a value of (the number of truepositives+the number of true negatives)/(the total number of cases). Theaccuracy indicates the ratio of samples that are identified correctly toall samples, and serves as a primary index for evaluating detectionperformance.

As used herein, the “sample” that is subject to determination,detection, or diagnosis refers to a tissue and a biological material inwhich the expression of the gene of the present invention varies aspancreatic cancer develops, as pancreatic cancer progresses, or astherapeutic effects on pancreatic cancer are exerted. Specifically, the“sample” refers to a pancreatic tissue, a peripancreatic vascularchannel, lymph node, and organ, an organ suspected of having metastasis,the skin, a body fluid such as blood, urine, saliva, sweat, or tissueexudates, serum or plasma prepared from blood, feces, hair, and thelike. The “sample” further refers to a biological sample extractedtherefrom, specifically, a gene such as RNA or miRNA.

The term “hsa-miR-6893-5p gene” or “hsa-miR-6893-5p” used hereinincludes the hsa-miR-6893-5p gene (miRBase Accession No. MIMAT0027686)described in SEQ ID NO: 1, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6893-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6893” (miRBase Accession No. MI0022740, SEQID NO: 123) having a hairpin-like structure is known as a precursor of“hsa-miR-6893-5p”.

The term “hsa-miR-6075 gene” or “hsa-miR-6075” used herein includes thehsa-miR-6075 gene (miRBase Accession No. MIMAT0023700) described in SEQID NO: 2, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-6075 gene can be obtained by a method described inVoellenkle C et al., 2012, RNA., Vol. 18, p. 472-484. Also,“hsa-mir-6075” (miRBase Accession No. MI0020352, SEQ ID NO: 124) havinga hairpin-like structure is known as a precursor of “hsa-miR-6075”.

The term “hsa-miR-6820-5p gene” or “hsa-miR-6820-5p” used hereinincludes the hsa-miR-6820-5p gene (miRBase Accession No. MIMAT0027540)described in SEQ ID NO: 3, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6820-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6820” (miRBase Accession No. MI0022665, SEQID NO: 125) having a hairpin-like structure is known as a precursor of“hsa-miR-6820-5p”.

The term “hsa-miR-4294 gene” or “hsa-miR-4294” used herein includes thehsa-miR-4294 gene (miRBase Accession No. MIMAT0016849) described in SEQID NO: 4, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4294 gene can be obtained by a method described inGoff L A et al., 2009, PLoS One., Vol. 4, e7192. Also, “hsa-mir-4294”(miRBase Accession No. MI0015827, SEQ ID NO: 126) having a hairpin-likestructure is known as a precursor of “hsa-miR-4294”.

The term “hsa-miR-6729-5p gene” or “hsa-miR-6729-5p” used hereinincludes the hsa-miR-6729-5p gene (miRBase Accession No. MIMAT0027359)described in SEQ ID NO: 5, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6729-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6729” (miRBase Accession No. MI0022574, SEQID NO: 127) having a hairpin-like structure is known as a precursor of“hsa-miR-6729-5p”.

The term “hsa-miR-4476 gene” or “hsa-miR-4476” used herein includes thehsa-miR-4476 gene (miRBase Accession No. MIMAT0019003) described in SEQID NO: 6, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4476 gene can be obtained by a method described inJima D D et al., 2010, Blood., Vol. 116, e118-e127. Also, “hsa-mir-4476”(miRBase Accession No. MI0016828, SEQ ID NO: 128) having a hairpin-likestructure is known as a precursor of “hsa-miR-4476”.

The term “hsa-miR-6836-3p gene” or “hsa-miR-6836-3p” used hereinincludes the hsa-miR-6836-3p gene (miRBase Accession No. MIMAT0027575)described in SEQ ID NO: 7, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6836-3p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6836” (miRBase Accession No. MI0022682, SEQID NO: 129) having a hairpin-like structure is known as a precursor of“hsa-miR-6836-3p”.

The term “hsa-miR-6765-3p gene” or “hsa-miR-6765-3p” used hereinincludes the hsa-miR-6765-3p gene (miRBase Accession No. MIMAT0027431)described in SEQ ID NO: 8, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6765-3p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6765” (miRBase Accession No. MI0022610, SEQID NO: 130) having a hairpin-like structure is known as a precursor of“hsa-miR-6765-3p”.

The term “hsa-miR-6799-5p gene” or “hsa-miR-6799-5p” used hereinincludes the hsa-miR-6799-5p gene (miRBase Accession No. MIMAT0027498)described in SEQ ID NO: 9, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6799-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6799” (miRBase Accession No. MI0022644, SEQID NO: 131) having a hairpin-like structure is known as a precursor of“hsa-miR-6799-5p”.

The term “hsa-miR-4530 gene” or “hsa-miR-4530” used herein includes thehsa-miR-4530 gene (miRBase Accession No. MIMAT0019069) described in SEQID NO: 10, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4530 gene can be obtained by a method describedinn Jima D D et al., 2010, Blood., Vol. 116, e118-e127. Also,“hsa-mir-4530” (miRBase Accession No. MI0016897, SEQ ID NO: 132) havinga hairpin-like structure is known as a precursor of “hsa-miR-4530”.

The term “hsa-miR-7641 gene” or “hsa-miR-7641” used herein includes thehsa-miR-7641 gene (miRBase Accession No. MIMAT0029782) described in SEQID NO: 11, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-7641 gene can be obtained by a method described inYoo J K et al., 2013, Arch Pharm Res., Vol. 36, p. 353-358. Also,“hsa-mir-7641-1 and hsa-mir-7641-2” (miRBase Accession Nos. MI0024975and MI0024976, SEQ ID NOs: 133 and 134) having a hairpin-like structureare known as precursors of “hsa-miR-7641”.

The term “hsa-miR-4454 gene” or “hsa-miR-4454” used herein includes thehsa-miR-4454 gene (miRBase Accession No. MIMAT0018976) described in SEQID NO: 12, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4454 gene can be obtained by a method described inJima D D et al., 2010, Blood., Vol. 116, e118-e127. Also, “hsa-mir-4454”(miRBase Accession No. MI0016800, SEQ ID NO: 135) having a hairpin-likestructure is known as a precursor of “hsa-miR-4454”.

The term “hsa-miR-615-5p gene” or “hsa-miR-615-5p” used in the presentspecification includes the hsa-miR-615-5p gene (miRBase Accession No.MIMAT0004804) described in SEQ ID NO: 13, a homolog or an ortholog of adifferent organism species, and the like. The hsa-miR-615-5p gene can beobtained by a method described in Cummins J M, 2006, Proc Natl Acad Sci,Vol. 103, p. 3687-3692. Also, “hsa-mir-615” (miRBase Accession No.MI0003628, SEQ ID NO: 136) having a hairpin-like structure is known as aprecursor of “hsa-miR-615-5p”.

The term “hsa-miR-8073 gene” or “hsa-miR-8073” used herein includes thehsa-miR-8073 gene (miRBase Accession No. MIMAT0031000) described in SEQID NO: 14, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-8073 gene can be obtained by a method described inWang H J et al., 2013, Shock., Vol. 39, p. 480-487. Also, “hsa-mir-8073”(miRBase Accession No. MI0025909, SEQ ID NO: 137) having a hairpin-likestructure is known as a precursor of “hsa-miR-8073”.

The term “hsa-miR-663a gene” or “hsa-miR-663a” used herein includes thehsa-miR-663a gene (miRBase Accession No. MIMAT0003326) described in SEQID NO: 15, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-663a gene can be obtained by a method described inCummins J M, 2006, Proc Natl Acad Sci, Vol. 103, p. 3687-3692. Also,“hsa-mir-663a” (miRBase Accession No. MI0003672, SEQ ID NO: 138) havinga hairpin-like structure is known as a precursor of “hsa-miR-663a”.

The term “hsa-miR-4634 gene” or “hsa-miR-4634” used herein includes thehsa-miR-4634 gene (miRBase Accession No. MIMAT0019691) described in SEQID NO: 16, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4634 gene can be obtained by a method described inPersson H et al., 2011, Cancer Res., Vol. 71, p. 78-86. Also,“hsa-mir-4634” (miRBase Accession No. MI0017261, SEQ ID NO: 139) havinga hairpin-like structure is known as a precursor of “hsa-miR-4634”.

The term “hsa-miR-4450 gene” or “hsa-miR-4450” used herein includes thehsa-miR-4450 gene (miRBase Accession No. MIMAT0018971) described in SEQID NO: 17, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4450 gene can be obtained by a method described inJima D D et al., 2010, Blood., Vol. 116, e118-e127. Also, “hsa-mir-4450”(miRBase Accession No. MI0016795, SEQ ID NO: 140) having a hairpin-likestructure is known as a precursor of “hsa-miR-4450”.

The term “hsa-miR-4792 gene” or “hsa-miR-4792” used herein includes thehsa-miR-4792 gene (miRBase Accession No. MIMAT0019964) described in SEQID NO: 18, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4792 gene can be obtained by a method described inPersson H et al., 2011, Cancer Res., Vol. 71, p. 78-86. Also,“hsa-mir-4792” (miRBase Accession No. MI0017439, SEQ ID NO: 141) havinga hairpin-like structure is known as a precursor of “hsa-miR-4792”.

The term “hsa-miR-665 gene” or “hsa-miR-665” used herein includes thehsa-miR-665 gene (miRBase Accession No. MIMAT0004952) described in SEQID NO: 19, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-665 gene can be obtained by a method described inBerezikov E et al., 2006, Genome Res., Vol. 16, p. 1289-1298. Also,“hsa-mir-665” (miRBase Accession No. MI0005563, SEQ ID NO: 142) having ahairpin-like structure is known as a precursor of “hsa-miR-665”.

The term “hsa-miR-7975 gene” or “hsa-miR-7975” used herein includes thehsa-miR-7975 gene (miRBase Accession No. MIMAT0031178) described in SEQID NO: 20, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-7975 gene can be obtained by a method described inVelthut-Meikas A et al., 2013, Mol Endocrinol.

[Epub prior to print]. Also, “hsa-mir-7975” (miRBase Accession No.MI0025751, SEQ ID NO: 143) having a hairpin-like structure is known as aprecursor of “hsa-miR-7975”.

The term “hsa-miR-7109-5p gene” or “hsa-miR-7109-5p” used hereinincludes the hsa-miR-7109-5p gene (miRBase Accession No. MIMAT0028115)described in SEQ ID NO: 21, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-7109-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-7109” (miRBase Accession No. MI0022960, SEQID NO: 144) having a hairpin-like structure is known as a precursor of“hsa-miR-7109-5p”.

The term “hsa-miR-6789-5p gene” or “hsa-miR-6789-5p” used hereinincludes the hsa-miR-6789-5p gene (miRBase Accession No. MIMAT0027478)described in SEQ ID NO: 22, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6789-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6789” (miRBase Accession No. MI0022634, SEQID NO: 145) having a hairpin-like structure is known as a precursor of“hsa-miR-6789-5p”.

The term “hsa-miR-4497 gene” or “hsa-miR-4497” used herein includes thehsa-miR-4497 gene (miRBase Accession No. MIMAT0019032) described in SEQID NO: 23, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4497 gene can be obtained by a method described inJima D D et al., 2010, Blood., Vol. 116, e118-e127. Also, “hsa-mir-4497”(miRBase Accession No. MI0016859, SEQ ID NO: 146) having a hairpin-likestructure is known as a precursor of “hsa-miR-4497”.

The term “hsa-miR-6877-5p gene” or “hsa-miR-6877-5p” used hereinincludes the hsa-miR-6877-5p gene (miRBase Accession No. MIMAT0027654)described in SEQ ID NO: 24, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6877-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6877” (miRBase Accession No. MI0022724, SEQID NO: 147) having a hairpin-like structure is known as a precursor of“hsa-miR-6877-5p”.

The term “hsa-miR-6880-5p gene” or “hsa-miR-6880-5p” used hereinincludes the hsa-miR-6880-5p gene (miRBase Accession No. MIMAT0027660)described in SEQ ID NO: 25, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6880-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6880” (miRBase Accession No. MI0022727, SEQID NO: 148) having a hairpin-like structure is known as a precursor of“hsa-miR-6880-5p”.

The term “hsa-miR-7977 gene” or “hsa-miR-7977” used herein includes thehsa-miR-7977 gene (miRBase Accession No. MIMAT0031180) described in SEQID NO: 26, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-7977 gene can be obtained by a method described inVelthut-Meikas A et al., 2013, Mol Endocrinol. [Epub prior to print].Also, “hsa-mir-7977” (miRBase Accession No. MI0025753, SEQ ID NO: 149)having a hairpin-like structure is known as a precursor of“hsa-miR-7977”.

The term “hsa-miR-4734 gene” or “hsa-miR-4734” used herein includes thehsa-miR-4734 gene (miRBase Accession No. MIMAT0019859) described in SEQID NO: 27, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4734 gene can be obtained by a method described inPersson H et al., 2011, Cancer Res., Vol. 71, p. 78-86. Also,“hsa-mir-4734” (miRBase Accession No. MI0017371, SEQ ID NO: 150) havinga hairpin-like structure is known as a precursor of “hsa-miR-4734”.

The term “hsa-miR-6821-5p gene” or “hsa-miR-6821-5p” used hereinincludes the hsa-miR-6821-5p gene (miRBase Accession No. MIMAT0027542)described in SEQ ID NO: 28, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6821-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6821” (miRBase Accession No. MI0022666, SEQID NO: 151) having a hairpin-like structure is known as a precursor of“hsa-miR-6821-5p”.

The term “hsa-miR-8089 gene” or “hsa-miR-8089” used herein includes thehsa-miR-8089 gene (miRBase Accession No. MIMAT0031016) described in SEQID NO: 29, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-8089 gene can be obtained by a method described inWang H J et al., 2013, Shock., Vol. 39, p. 480-487. Also, “hsa-mir-8089”(miRBase Accession No. MI0025925, SEQ ID NO: 152) having a hairpin-likestructure is known as a precursor of “hsa-miR-8089”.

The term “hsa-miR-5585-3p gene” or “hsa-miR-5585-3p” used hereinincludes the hsa-miR-5585-3p gene (miRBase Accession No. MIMAT0022286)described in SEQ ID NO: 30, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-5585-3p gene can be obtainedby a method described in Friedlander M R et al., 2012, Nucleic AcidsRes., Vol. 40, p. 37-52. Also, “hsa-mir-5585” (miRBase Accession No.MI0019142, SEQ ID NO: 153) having a hairpin-like structure is known as aprecursor of “hsa-miR-5585-3p”.

The term “hsa-miR-6085 gene” or “hsa-miR-6085” used herein includes thehsa-miR-6085 gene (miRBase Accession No. MIMAT0023710) described in SEQID NO: 31, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-6085 gene can be obtained by a method described inVoellencle C et al., 2012, RNA., Vol. 18, p. 472-484. Also,“hsa-mir-6085” (miRBase Accession No. MI0020362, SEQ ID NO: 154) havinga hairpin-like structure is known as a precursor of “hsa-miR-6085”.

The term “hsa-miR-6845-5p gene” or “hsa-miR-6845-5p” used hereinincludes the hsa-miR-6845-5p gene (miRBase Accession No. MIMAT0027590)described in SEQ ID NO: 32, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6845-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6845” (miRBase Accession No. MI0022691, SEQID NO: 155) having a hairpin-like structure is known as a precursor of“hsa-miR-6845-5p”.

The term “hsa-miR-4651 gene” or “hsa-miR-4651” used herein includes thehsa-miR-4651 gene (miRBase Accession No. MIMAT0019715) described in SEQID NO: 33, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4651 gene can be obtained by a method described inPersson H et al., 2011, Cancer Res., Vol. 71, p. 78-86. Also,“hsa-mir-4651” (miRBase Accession No. MI0017279, SEQ ID NO: 156) havinga hairpin-like structure is known as a precursor of “hsa-miR-4651”.

The term “hsa-miR-4433-3p gene” or “hsa-miR-4433-3p” used hereinincludes the hsa-miR-4433-3p gene (miRBase Accession No. MIMAT0018949)described in SEQ ID NO: 34, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-4433-3p gene can be obtainedby a method described in Jima D D et al., 2010, Blood., Vol. 116,e118-e127. Also, “hsa-mir-4433” (miRBase Accession No. MI0016773, SEQ IDNO: 157) having a hairpin-like structure is known as a precursor of“hsa-miR-4433-3p”.

The term “hsa-miR-1231 gene” or “hsa-miR-1231” used herein includes thehsa-miR-1231 gene (miRBase Accession No. MIMAT0005586) described in SEQID NO: 35, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-1231 gene can be obtained by a method described inBerezikov E et al., 2007, Mol Cell., Vol. 28, p. 328-336. Also,“hsa-mir-1231” (miRBase Accession No. MI0006321, SEQ ID NO: 158) havinga hairpin-like structure is known as a precursor of “hsa-miR-1231”.

The term “hsa-miR-4665-5p gene” or “hsa-miR-4665-5p” used hereinincludes the hsa-miR-4665-5p gene (miRBase Accession No. MIMAT0019739)described in SEQ ID NO: 36, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-4665-5p gene can be obtainedby a method described in Persson H et al., 2011, Cancer Res., Vol. 71,p. 78-86. Also, “hsa-mir-4665” (miRBase Accession No. MI0017295, SEQ IDNO: 159) having a hairpin-like structure is known as a precursor of“hsa-miR-4665-5p”.

The term “hsa-miR-7114-5p gene” or “hsa-miR-7114-5p” used hereinincludes the hsa-miR-7114-5p gene (miRBase Accession No. MIMAT0028125)described in SEQ ID NO: 37, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-7114-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-7114” (miRBase Accession No. MI0022965, SEQID NO: 160) having a hairpin-like structure is known as a precursor of“hsa-miR-7114-5p”.

The term “hsa-miR-1238-5p gene” or “hsa-miR-1238-5p” used hereinincludes the hsa-miR-1238-5p gene (miRBase Accession No. MIMAT0022947)described in SEQ ID NO: 38, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-1238-5p gene can be obtainedby a method described in Berezikov E et al., 2007, Mol Cell., Vol. 28,p. 328-336. Also, “hsa-mir-1238” (miRBase Accession No. MI0006328, SEQID NO: 161) having a hairpin-like structure is known as a precursor of“hsa-miR-1238-5p”.

The term “hsa-miR-8069 gene” or “hsa-miR-8069” used herein includes thehsa-miR-8069 gene (miRBase Accession No. MIMAT0030996) described in SEQID NO: 39, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-8069 gene can be obtained by a method described inWang H J et al., 2013, Shock., Vol. 39, p. 480-487. Also, “hsa-mir-8069”(miRBase Accession No. MI0025905, SEQ ID NO: 162) having a hairpin-likestructure is known as a precursor of “hsa-miR-8069”.

The term “hsa-miR-4732-5p gene” or “hsa-miR-4732-5p” used hereinincludes the hsa-miR-4732-5p gene (miRBase Accession No. MIMAT0019855)described in SEQ ID NO: 40, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-4732-5p gene can be obtainedby a method described in Persson H et al., 2011, Cancer Res., Vol. 71,p. 78-86. Also, “hsa-mir-4732” (miRBase Accession No. MI0017369, SEQ IDNO: 163) having a hairpin-like structure is known as a precursor of“hsa-miR-4732-5p”.

The term “hsa-miR-619-5p gene” or “hsa-miR-619-5p” used herein includesthe hsa-miR-619-5p gene (miRBase Accession No. MIMAT0026622) describedin SEQ ID NO: 41, a homolog or an ortholog of a different organismspecies, and the like. The hsa-miR-619-5p gene can be obtained by amethod described in Cummins J M, 2006, Proc Natl Acad Sci, Vol. 103, p.3687-3692. Also, “hsa-mir-619” (miRBase Accession No. MI0003633, SEQ IDNO: 164) having a hairpin-like structure is known as a precursor of“hsa-miR-619-5p”.

The term “hsa-miR-3622a-5p gene” or “hsa-miR-3622a-5p” used hereinincludes the hsa-miR-3622a-5p gene (miRBase Accession No. MIMAT0018003)described in SEQ ID NO: 42, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-3622a-5p gene can beobtained by a method described in Witten D et al., 2010, BMC Biol., Vol.8, p. 58. Also, “hsa-mir-3622a” (miRBase Accession No. MI0016013, SEQ IDNO: 165) having a hairpin-like structure is known as a precursor of“hsa-miR-3622a-5p”.

The term “hsa-miR-1260a gene” or “hsa-miR-1260a” used herein includesthe hsa-miR-1260a gene (miRBase Accession No. MIMAT0005911) described inSEQ ID NO: 43, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-1260a gene can be obtained by a methoddescribed in Morin R D et al., 2008, Genome Res., Vol. 18, p. 610-621.Also, “hsa-mir-1260a” (miRBase Accession No. MI0006394, SEQ ID NO: 166)having a hairpin-like structure is known as a precursor of“hsa-miR-1260a”.

The term “hsa-miR-6741-5p gene” or “hsa-miR-6741-5p” used hereinincludes the hsa-miR-6741-5p gene (miRBase Accession No. MIMAT0027383)described in SEQ ID NO: 44, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6741-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6741” (miRBase Accession No. MI0022586, SEQID NO: 167) having a hairpin-like structure is known as a precursor of“hsa-miR-6741-5p”.

The term “hsa-miR-6781-5p gene” or “hsa-miR-6781-5p” used hereinincludes the hsa-miR-6781-5p gene (miRBase Accession No. MIMAT0027462)described in SEQ ID NO: 45, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6781-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6781” (miRBase Accession No. MI0022626, SEQID NO: 168) having a hairpin-like structure is known as a precursor of“hsa-miR-6781-5p”.

The term “hsa-miR-6125 gene” or “hsa-miR-6125” used herein includes thehsa-miR-6125 gene (miRBase Accession No. MIMAT0024598) described in SEQID NO: 46, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-6125 gene can be obtained by a method described inSmith J L et al., 2012, J Virol., Vol. 86, p. 5278-5287. Also,“hsa-mir-6125” (miRBase Accession No. MI0021259, SEQ ID NO: 169) havinga hairpin-like structure is known as a precursor of “hsa-miR-6125”.

The term “hsa-miR-6805-5p gene” or “hsa-miR-6805-5p” used hereinincludes the hsa-miR-6805-5p gene (miRBase Accession No. MIMAT0027510)described in SEQ ID NO: 47, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6805-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6805” (miRBase Accession No. MI0022650, SEQID NO: 170) having a hairpin-like structure is known as a precursor of“hsa-miR-6805-5p”.

The term “hsa-miR-6132 gene” or “hsa-miR-6132” used herein includes thehsa-miR-6132 gene (miRBase Accession No. MIMAT0024616) described in SEQID NO: 48, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-6132 gene can be obtained by a method described inDannemann M, 2012, Genome Biol Evol., Vol. 4, p. 552-564. Also,“hsa-mir-6132” (miRBase Accession No. MI0021277, SEQ ID NO: 171) havinga hairpin-like structure is known as a precursor of “hsa-miR-6132”.

The term “hsa-miR-6872-3p gene” or “hsa-miR-6872-3p” used hereinincludes the hsa-miR-6872-3p gene (miRBase Accession No. MIMAT0027645)described in SEQ ID NO: 49, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6872-3p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6872” (miRBase Accession No. MI0022719, SEQID NO: 172) having a hairpin-like structure is known as a precursor of“hsa-miR-6872-3p”.

The term “hsa-miR-6875-5p gene” or “hsa-miR-6875-5p” used hereinincludes the hsa-miR-6875-5p gene (miRBase Accession No. MIMAT0027650)described in SEQ ID NO: 50, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6875-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6875” (miRBase Accession No. MI0022722, SEQID NO: 173) having a hairpin-like structure is known as a precursor of“hsa-miR-6875-5p”.

The term “hsa-miR-1908-3p gene” or “hsa-miR-1908-3p” used hereinincludes the hsa-miR-1908-3p gene (miRBase Accession No. MIMAT0026916)described in SEQ ID NO: 51, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-1908-3p gene can be obtainedby a method described in Bar M et al., 2008, Stem Cells., Vol. 26, p.2496-2505. Also, “hsa-mir-1908” (miRBase Accession No. MI0008329, SEQ IDNO: 174) having a hairpin-like structure is known as a precursor of“hsa-miR-1908-3p”.

The term “hsa-miR-4433b-3p gene” or “hsa-miR-4433b-3p” used hereinincludes the hsa-miR-4433b-3p gene (miRBase Accession No. MIMAT0030414)described in SEQ ID NO: 52, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-4433b-3p gene can beobtained by a method described in Ple H et al., 2012, PLoS One.,

Vol. 7, e50746. Also, “hsa-mir-4433b” (miRBase Accession No. MI0025511,SEQ ID NO: 175) having a hairpin-like structure is known as a precursorof “hsa-miR-4433b-3p”.

The term “hsa-miR-4736 gene” or “hsa-miR-4736” used herein includes thehsa-miR-4736 gene (miRBase Accession No. MIMAT0019862) described in SEQID NO: 53, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4736 gene can be obtained by a method described inPersson H et al., 2011, Cancer Res., Vol. 71, p. 78-86. Also,“hsa-mir-4736” (miRBase Accession No. MI0017373, SEQ ID NO: 176) havinga hairpin-like structure is known as a precursor of “hsa-miR-4736”.

The term “hsa-miR-5100 gene” or “hsa-miR-5100” used herein includes thehsa-miR-5100 gene (miRBase Accession No. MIMAT0022259) described in SEQID NO: 54, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-5100 gene can be obtained by a method described inTandon M et al., 2012, Oral Dis., Vol. 18, p. 127-131. Also,“hsa-mir-5100” (miRBase Accession No. MI0019116, SEQ ID NO: 177) havinga hairpin-like structure is known as a precursor of “hsa-miR-5100”.

The term “hsa-miR-6724-5p gene” or “hsa-miR-6724-5p” used hereinincludes the hsa-miR-6724-5p gene (miRBase Accession No. MIMAT0025856)described in SEQ ID NO: 55 a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6724-5p gene can be obtainedby a method described in Li Y et al., 2012, Gene., Vol. 497, p. 330-335.Also, “hsa-mir-6724” (miRBase Accession No. MI0022559, SEQ ID NO: 178)having a hairpin-like structure is known as a precursor of“hsa-miR-6724-5p”.

The term “hsa-miR-7107-5p gene” or “hsa-miR-7107-5p” used hereinincludes the hsa-miR-7107-5p gene (miRBase Accession No. MIMAT0028111)described in SEQ ID NO: 56, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-7107-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-7107” (miRBase Accession No. MI0022958, SEQID NO: 179) having a hairpin-like structure is known as a precursor of“hsa-miR-7107-5p”.

The term “hsa-miR-6726-5p gene” or “hsa-miR-6726-5p” used hereinincludes the hsa-miR-6726-5p gene (miRBase Accession No. MIMAT0027353)described in SEQ ID NO: 57, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6726-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6726” (miRBase Accession No. MI0022571, SEQID NO: 180) having a hairpin-like structure is known as a precursor of“hsa-miR-6726-5p”.

The term “hsa-miR-3185 gene” or “hsa-miR-3185” used herein includes thehsa-miR-3185 gene (miRBase Accession No. MIMAT0015065) described in SEQID NO: 58, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-3185 gene can be obtained by a method described inStark M S et al., 2010, PLoS One., Vol. 5, e9685. Also, “hsa-mir-3185”(miRBase Accession No. MI0014227, SEQ ID NO: 181) having a hairpin-likestructure is known as a precursor of “hsa-miR-3185”.

The term “hsa-miR-4638-5p gene” or “hsa-miR-4638-5p” used hereinincludes the hsa-miR-4638-5p gene (miRBase Accession No. MIMAT0019695)described in SEQ ID NO: 59, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-4638-5p gene can be obtainedby a method described in Persson H et al., 2011, Cancer Res., Vol. 71,p. 78-86. Also, “hsa-mir-4638” (miRBase Accession No. MI0017265, SEQ IDNO: 182) having a hairpin-like structure is known as a precursor of“hsa-miR-4638-5p”.

The term “hsa-miR-1273g-3p gene” or “hsa-miR-1273g-3p” used hereinincludes the hsa-miR-1273g-3p gene (miRBase Accession No. MIMAT0022742)described in SEQ ID NO: 60, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-1273g-3p gene can beobtained by a method described in Reshmi G et al., 2011, Genomics., Vol.97, p. 333-340. Also, “hsa-mir-1273g” (miRBase Accession No. MI0018003,SEQ ID NO: 183) having a hairpin-like structure is known as a precursorof “hsa-miR-1273g-3p”.

The term “hsa-miR-6778-5p gene” or “hsa-miR-6778-5p” used hereinincludes the hsa-miR-6778-5p gene (miRBase Accession No. MIMAT0027456)described in SEQ ID NO: 61, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6778-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6778” (miRBase Accession No. MI0022623, SEQID NO: 184) having a hairpin-like structure is known as a precursor of“hsa-miR-6778-5p”.

The term “hsa-miR-328-5p gene” or “hsa-miR-328-5p” used herein includesthe hsa-miR-328-5p gene (miRBase Accession No. MIMAT0026486) describedin SEQ ID NO: 62, a homolog or an ortholog of a different organismspecies, and the like. The hsa-miR-328-5p gene can be obtained by amethod described in Kim J et al., 2004, Proc Natl Acad Sci, Vol. 101, p.360-365. Also, “hsa-mir-328” (miRBase Accession No. MI0000804, SEQ IDNO: 185) having a hairpin-like structure is known as a precursor of“hsa-miR-328-5p”.

The term “hsa-miR-3679-3p gene” or “hsa-miR-3679-3p” used hereinincludes the hsa-miR-3679-3p gene (miRBase Accession No. MIMAT0018105)described in SEQ ID NO: 63, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-3679-3p gene can be obtainedby a method described in Creighton C J et al., 2010, PLoS One., Vol. 5,e9637. Also, “hsa-mir-3679” (miRBase Accession No. MI0016080, SEQ ID NO:186) having a hairpin-like structure is known as a precursor of“hsa-miR-3679-3p”.

The term “hsa-miR-1228-3p gene” or “hsa-miR-1228-3p” used hereinincludes the hsa-miR-1228-3p gene (miRBase Accession No. MIMAT0005583)described in SEQ ID NO: 64, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-1228-3p gene can be obtainedby a method described in Berezikov E et al., 2007, Mol Cell., Vol. 28,p. 328-336. Also, “hsa-mir-1228” (miRBase Accession No. MI0006318, SEQID NO: 187) having a hairpin-like structure is known as a precursor of“hsa-miR-1228-3p”.

The term “hsa-miR-6779-5p gene” or “hsa-miR-6779-5p” used hereinincludes the hsa-miR-6779-5p gene (miRBase Accession No. MIMAT0027458)described in SEQ ID NO: 65, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6779-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6779” (miRBase Accession No. MI0022624, SEQID NO: 188) having a hairpin-like structure is known as a precursor of“hsa-miR-6779-5p”.

The term “hsa-miR-4723-5p gene” or “hsa-miR-4723-5p” used hereinincludes the hsa-miR-4723-5p gene (miRBase Accession No. MIMAT0019838)described in SEQ ID NO: 66, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-4723-5p gene can be obtainedby a method described in Persson H et al., 2011, Cancer Res., Vol. 71,p. 78-86. Also, “hsa-mir-4723” (miRBase Accession No. MI0017359, SEQ IDNO: 189) having a hairpin-like structure is known as a precursor of“hsa-miR-4723-5p”.

The term “hsa-miR-6850-5p gene” or “hsa-miR-6850-5p” used hereinincludes the hsa-miR-6850-5p gene (miRBase Accession No. MIMAT0027600)described in SEQ ID NO: 67, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6850-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6850” (miRBase Accession No. MI0022696, SEQID NO: 190) having a hairpin-like structure is known as a precursor of“hsa-miR-6850-5p”.

The term “hsa-miR-760 gene” or “hsa-miR-760” used herein includes thehsa-miR-760 gene (miRBase Accession No. MIMAT0004957) described in SEQID NO: 68, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-760 gene can be obtained by a method described inBerezikov E et al., 2006, Genome Res., Vol. 16, p. 1289-1298. Also,“hsa-mir-760” (miRBase Accession No. MI0005567, SEQ ID NO: 191) having ahairpin-like structure is known as a precursor of “hsa-miR-760”.

The term “hsa-miR-7704 gene” or “hsa-miR-7704” used herein includes thehsa-miR-7704 gene (miRBase Accession No. MIMAT0030019) described in SEQID NO: 69, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-7704 gene can be obtained by a method described inSwaminathan S et al., 2013, Biochem Biophys Res Commun., Vol. 434, p.228-234. Also, “hsa-mir-7704” (miRBase Accession No. MI0025240, SEQ IDNO: 192) having a hairpin-like structure is known as a precursor of“hsa-miR-7704”.

The term “hsa-miR-8072 gene” or “hsa-miR-8072” used herein includes thehsa-miR-8072 gene (miRBase Accession No. MIMAT0030999) described in SEQID NO: 70, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-8072 gene can be obtained by a method described inWang H J et al., 2013, Shock., Vol. 39, p. 480-487. Also, “hsa-mir-8072”(miRBase Accession No. MI0025908, SEQ ID NO: 193) having a hairpin-likestructure is known as a precursor of “hsa-miR-8072”.

The term “hsa-miR-4486 gene” or “hsa-miR-4486” used herein includes thehsa-miR-4486 gene (miRBase Accession No. MIMAT0019020) described in SEQID NO: 71, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4486 gene can be obtained by a method described inJima D D et al., 2010, Blood., Vol. 116, e118-e127. Also, “hsa-mir-4486”(miRBase Accession No. MI0016847, SEQ ID NO: 194) having a hairpin-likestructure is known as a precursor of “hsa-miR-4486”.

The term “hsa-miR-1913 gene” or “hsa-miR-1913” used herein includes thehsa-miR-1913 gene (miRBase Accession No. MIMAT0007888) described in SEQID NO: 72, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-1913 gene can be obtained by a method described inBar M et al., 2008, Stem Cells., Vol. 26, p. 2496-2505. Also,“hsa-mir-1913” (miRBase Accession No. MI0008334, SEQ ID NO: 195) havinga hairpin-like structure is known as a precursor of “hsa-miR-1913”.

The term “hsa-miR-4656 gene” or “hsa-miR-4656” used herein includes thehsa-miR-4656 gene (miRBase Accession No. MIMAT0019723) described in SEQID NO: 73, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4656 gene can be obtained by a method described inPersson H et al., 2011, Cancer Res., Vol. 71, p. 78-86. Also,“hsa-mir-4656” (miRBase Accession No. MI0017284, SEQ ID NO: 196) havinga hairpin-like structure is known as a precursor of “hsa-miR-4656”.

The term “hsa-miR-1260b gene” or “hsa-miR-1260b” used herein includesthe hsa-miR-1260b gene (miRBase Accession No. MIMAT0015041) described inSEQ ID NO: 74, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-1260b gene can be obtained by a methoddescribed in Stark M S et al., 2010, PLoS One., Vol. 5, e9685. Also,“hsa-mir-1260b” (miRBase Accession No. MI0014197, SEQ ID NO: 197) havinga hairpin-like structure is known as a precursor of “hsa-miR-1260b”.

The term “hsa-miR-7106-5p gene” or “hsa-miR-7106-5p” used hereinincludes the hsa-miR-7106-5p gene (miRBase Accession No. MIMAT0028109)described in SEQ ID NO: 75, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-7106-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-7106” (miRBase Accession No. MI0022957, SEQID NO: 198) having a hairpin-like structure is known as a precursor of“hsa-miR-7106-5p”.

The term “hsa-miR-6889-5p gene” or “hsa-miR-6889-5p” used hereinincludes the hsa-miR-6889-5p gene (miRBase Accession No. MIMAT0027678)described in SEQ ID NO: 76, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6889-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6889” (miRBase Accession No. MI0022736, SEQID NO: 199) having a hairpin-like structure is known as a precursor of“hsa-miR-6889-5p”.

The term “hsa-miR-6780b-5p gene” or “hsa-miR-6780b-5p” used hereinincludes the hsa-miR-6780b-5p gene (miRBase Accession No. MIMAT0027572)described in SEQ ID NO: 77, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6780b-5p gene can beobtained by a method described in Ladewig E et al., 2012, Genome Res.,Vol. 22, p. 1634-1645. Also, “hsa-mir-6780b” (miRBase Accession No.MI0022681, SEQ ID NO: 200) having a hairpin-like structure is known as aprecursor of “hsa-miR-6780b-5p”.

The term “hsa-miR-6090 gene” or “hsa-miR-6090” used herein includes thehsa-miR-6090 gene (miRBase Accession No. MIMAT0023715) described in SEQID NO: 78, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-6090 gene can be obtained by a method described inYoo J K et al., 2013, Arch Pharm Res., Vol. 36, p. 353-358. Also,“hsa-mir-6090” (miRBase Accession No. MI0020367, SEQ ID NO: 201) havinga hairpin-like structure is known as a precursor of “hsa-miR-6090”.

The term “hsa-miR-4534 gene” or “hsa-miR-4534” used herein includes thehsa-miR-4534 gene (miRBase Accession No. MIMAT0019073) described in SEQID NO: 79, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4534 gene can be obtained by a method described inJima D D et al., 2010, Blood., Vol. 116, e118-e127. Also, “hsa-mir-4534”(miRBase Accession No. MI0016901, SEQ ID NO: 202) having a hairpin-likestructure is known as a precursor of “hsa-miR-4534”.

The term “hsa-miR-4449 gene” or “hsa-miR-4449” used herein includes thehsa-miR-4449 gene (miRBase Accession No. MIMAT0018968) described in SEQID NO: 80, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4449 gene can be obtained by a method described inJima D D et al., 2010, Blood., Vol. 116, e118-e127. Also, “hsa-mir-4449”(miRBase Accession No. MI0016792, SEQ ID NO: 203) having a hairpin-likestructure is known as a precursor of “hsa-miR-4449”.

The term “hsa-miR-5195-3p gene” or “hsa-miR-5195-3p” used hereinincludes the hsa-miR-5195-3p gene (miRBase Accession No. MIMAT0021127)described in SEQ ID NO: 81, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-5195-3p gene can be obtainedby a method described in Schotte D et al., 2011, Leukemia., Vol. 25, p.1389-1399. Also, “hsa-mir-5195” (miRBase Accession No. MI0018174, SEQ IDNO: 204) having a hairpin-like structure is known as a precursor of“hsa-miR-5195-3p”.

The term “hsa-miR-1202 gene” or “hsa-miR-1202” used herein includes thehsa-miR-1202 gene (miRBase Accession No. MIMAT0005865) described in SEQID NO: 82, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-1202 gene can be obtained by a method described inMarton S et al., 2008, Leukemia., Vol. 22, p. 330-338. Also,“hsa-mir-1202” (miRBase Accession No. MI0006334, SEQ ID NO: 205) havinga hairpin-like structure is known as a precursor of “hsa-miR-1202”.

The term “hsa-miR-4467 gene” or “hsa-miR-4467” used herein includes thehsa-miR-4467 gene (miRBase Accession No. MIMAT0018994) described in SEQID NO: 83, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4467 gene can be obtained by a method described inJima D D et al., 2010, Blood., Vol. 116, e118-e127. Also, “hsa-mir-4467”(miRBase Accession No. MI0016818, SEQ ID NO: 206) having a hairpin-likestructure is known as a precursor of “hsa-miR-4467”.

The term “hsa-miR-6515-3p gene” or “hsa-miR-6515-3p” used hereinincludes the hsa-miR-6515-3p gene (miRBase Accession No. MIMAT0025487)described in SEQ ID NO: 84, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6515-3p gene can be obtainedby a method described in Joyce C E et al., 2011, Hum Mol Genet., Vol.20, p. 4025-4040. Also, “hsa-mir-6515” (miRBase Accession No. MI0022227,SEQ ID NO: 207) having a hairpin-like structure is known as a precursorof “hsa-miR-6515-3p”.

The term “hsa-miR-4281 gene” or “hsa-miR-4281” used herein includes thehsa-miR-4281 gene (miRBase Accession No. MIMAT0016907) described in SEQID NO: 85, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4281 gene can be obtained by a method described inGoff L A et al., 2009, PLoS One., Vol. 4, e7192. Also, “hsa-mir-4281”(miRBase Accession No. MI0015885, SEQ ID NO: 208) having a hairpin-likestructure is known as a precursor of “hsa-miR-4281”.

The term “hsa-miR-4505 gene” or “hsa-miR-4505” used herein includes thehsa-miR-4505 gene (miRBase Accession No. MIMAT0019041) described in SEQID NO: 86, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4505 gene can be obtained by a method described inJima D D et al., 2010, Blood., Vol. 116, e118-e127. Also, “hsa-mir-4505”(miRBase Accession No. MI0016868, SEQ ID NO: 209) having a hairpin-likestructure is known as a precursor of “hsa-miR-4505”.

The term “hsa-miR-4484 gene” or “hsa-miR-4484” used herein includes thehsa-miR-4484 gene (miRBase Accession No. MIMAT0019018) described in SEQID NO: 87, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4484 gene can be obtained by a method described inJima D D et al., 2010, Blood., Vol. 116, e118-e127. Also, “hsa-mir-4484”(miRBase Accession No. MI0016845, SEQ ID NO: 210) having a hairpin-likestructure is known as a precursor of “hsa-miR-4484”.

The term “hsa-miR-6805-3p gene” or “hsa-miR-6805-3p” used hereinincludes the hsa-miR-6805-3p gene (miRBase Accession No. MIMAT0027511)described in SEQ ID NO: 88, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6805-3p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6805” (miRBase Accession No. MI0022650, SEQID NO: 211) having a hairpin-like structure is known as a precursor of“hsa-miR-6805-3p”.

The term “hsa-miR-3135b gene” or “hsa-miR-3135b” used herein includesthe hsa-miR-3135b gene (miRBase Accession No. MIMAT0018985) described inSEQ ID NO: 89, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-3135b gene can be obtained by a methoddescribed in Jima D D et al., 2010, Blood., Vol. 116, e118-e127. Also,“hsa-mir-3135b” (miRBase Accession No. MI0016809, SEQ ID NO: 212) havinga hairpin-like structure is known as a precursor of “hsa-miR-3135b”.

The term “hsa-miR-3162-5p gene” or “hsa-miR-3162-5p” used hereinincludes the hsa-miR-3162-5p gene (miRBase Accession No. MIMAT0015036)described in SEQ ID NO: 90, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-3162-5p gene can be obtainedby a method described in Stark M S et al., 2010, PLoS One., Vol. 5,e9685. Also, “hsa-mir-3162” (miRBase Accession No. MI0014192, SEQ ID NO:213) having a hairpin-like structure is known as a precursor of“hsa-miR-3162-5p”.

The term “hsa-miR-6768-5p gene” or “hsa-miR-6768-5p” used hereinincludes the hsa-miR-6768-5p gene (miRBase Accession No. MIMAT0027436)described in SEQ ID NO: 91, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6768-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6768” (miRBase Accession No. MI0022613, SEQID NO: 214) having a hairpin-like structure is known as a precursor of“hsa-miR-6768-5p”.

The term “hsa-miR-6721-5p gene” or “hsa-miR-6721-5p” used hereinincludes the hsa-miR-6721-5p gene (miRBase Accession No. MIMAT0025852)described in SEQ ID NO: 92, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6721-5p gene can be obtainedby a method described in Li Y et al., 2012, Gene., Vol. 497, p. 330-335.Also, “hsa-mir-6721” (miRBase Accession No. MI0022556, SEQ ID NO: 215)having a hairpin-like structure is known as a precursor of“hsa-miR-6721-5p”.

The term “hsa-miR-1227-5p gene” or “hsa-miR-1227-5p” used hereinincludes the hsa-miR-1227-5p gene (miRBase Accession No. MIMAT0022941)described in SEQ ID NO: 93, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-1227-5p gene can be obtainedby a method described in Berezikov E et al., 2007, Mol Cell., Vol. 28,p. 328-336. Also, “hsa-mir-1227” (miRBase Accession No. MI0006316, SEQID NO: 216) having a hairpin-like structure is known as a precursor of“hsa-miR-1227-5p”.

The term “hsa-miR-6722-3p gene” or “hsa-miR-6722-3p” used hereinincludes the hsa-miR-6722-3p gene (miRBase Accession No. MIMAT0025854)described in SEQ ID NO: 94, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6722-3p gene can be obtainedby a method described in Li Y et al., 2012, Gene., Vol. 497, p. 330-335.Also, “hsa-mir-6722” (miRBase Accession No. MI0022557, SEQ ID NO: 217)having a hairpin-like structure is known as a precursor of“hsa-miR-6722-3p”.

The term “hsa-miR-4286 gene” or “hsa-miR-4286” used herein includes thehsa-miR-4286 gene (miRBase Accession No. MIMAT0016916) described in SEQID NO: 95, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4286 gene can be obtained by a method described inGoff L A et al., 2009, PLoS One., Vol. 4, e7192. Also, “hsa-mir-4286”(miRBase Accession No. MI0015894, SEQ ID NO: 218) having a hairpin-likestructure is known as a precursor of “hsa-miR-4286”.

The term “hsa-miR-4746-3p gene” or “hsa-miR-4746-3p” used hereinincludes the hsa-miR-4746-3p gene (miRBase Accession No. MIMAT0019881)described in SEQ ID NO: 96, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-4746-3p gene can be obtainedby a method described in Persson H et al., 2011, Cancer Res., Vol. 71,p. 78-86. Also, “hsa-mir-4746” (miRBase Accession No. MI0017385, SEQ IDNO: 219) having a hairpin-like structure is known as a precursor of“hsa-miR-4746-3p”.

The term “hsa-miR-6727-5p gene” or “hsa-miR-6727-5p” used hereinincludes the hsa-miR-6727-5p gene (miRBase Accession No. MIMAT0027355)described in SEQ ID NO: 97, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6727-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6727” (miRBase Accession No. MI0022572, SEQID NO: 220) having a hairpin-like structure is known as a precursor of“hsa-miR-6727-5p”.

The term “hsa-miR-6816-5p gene” or “hsa-miR-6816-5p” used hereinincludes the hsa-miR-6816-5p gene (miRBase Accession No. MIMAT0027532)described in SEQ ID NO: 98, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6816-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6816” (miRBase Accession No. MI0022661, SEQID NO: 221) having a hairpin-like structure is known as a precursor of“hsa-miR-6816-5p”.

The term “hsa-miR-4741 gene” or “hsa-miR-4741” used herein includes thehsa-miR-4741 gene (miRBase Accession No. MIMAT0019871) described in SEQID NO: 99, a homolog or an ortholog of a different organism species, andthe like. The hsa-miR-4741 gene can be obtained by a method described inPersson H et al., 2011, Cancer Res., Vol. 71, p. 78-86. Also,“hsa-mir-4741” (miRBase Accession No. MI0017379, SEQ ID NO: 222) havinga hairpin-like structure is known as a precursor of “hsa-miR-4741”.

The term “hsa-miR-4508 gene” or “hsa-miR-4508” used herein includes thehsa-miR-4508 gene (miRBase Accession No. MIMAT0019045) described in SEQID NO: 100, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-4508 gene can be obtained by a methoddescribed in Jima D D et al., 2010, Blood., Vol. 116, e118-e127. Also,“hsa-mir-4508” (miRBase Accession No. MI0016872, SEQ ID NO: 223) havinga hairpin-like structure is known as a precursor of “hsa-miR-4508”.

The term “hsa-miR-940 gene” or “hsa-miR-940” used herein includes thehsa-miR-940 gene (miRBase Accession No. MIMAT0004983) described in SEQID NO: 101, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-940 gene can be obtained by a method describedin Lui W O et al., 2007, A Cancer Res., Vol. 67, p. 6031-6043. Also,“hsa-mir-940” (miRBase Accession No. MI0005762, SEQ ID NO: 224) having ahairpin-like structure is known as a precursor of “hsa-miR-940”.

The term “hsa-miR-4327 gene” or “hsa-miR-4327” used herein includes thehsa-miR-4327 gene (miRBase Accession No. MIMAT0016889) described in SEQID NO: 102, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-4327 gene can be obtained by a methoddescribed in Goff L A et al., 2009, PLoS One., Vol. 4, e7192. Also,“hsa-mir-4327” (miRBase Accession No. MI0015867, SEQ ID NO: 225) havinga hairpin-like structure is known as a precursor of “hsa-miR-4327”.

The term “hsa-miR-4665-3p gene” or “hsa-miR-4665-3p” used hereinincludes the hsa-miR-4665-3p gene (miRBase Accession No. MIMAT0019740)described in SEQ ID NO: 103, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-4665-3p gene can be obtainedby a method described in Persson H et al., 2011, Cancer Res., Vol. 71,p. 78-86. Also, “hsa-mir-4665” (miRBase Accession No. MI0017295, SEQ IDNO: 159) having a hairpin-like structure is known as a precursor of“hsa-miR-4665-3p”.

The term “hsa-miR-718 gene” or “hsa-miR-718” used herein includes thehsa-miR-718 gene (miRBase Accession No. MIMAT0012735) described in SEQID NO: 104, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-718 gene can be obtained by a method describedin Artzi S et al., 2008, BMC Bioinformatics., Vol. 9, p. 39. Also,“hsa-mir-718” (miRBase Accession No. MI0012489, SEQ ID NO: 226) having ahairpin-like structure is known as a precursor of “hsa-miR-718”.

The term “hsa-miR-125a-3p gene” or “hsa-miR-125a-3p” used hereinincludes the hsa-miR-125a-3p gene (miRBase Accession No. MIMAT0004602)described in SEQ ID NO: 105, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-125a-3p gene can be obtainedby a method described in Lagos-Quintana M et al., 2002, Curr Biol., Vol.12, p. 735-739. Also, “hsa-mir-125a” (miRBase Accession No. MI0000469,SEQ ID NO: 227) having a hairpin-like structure is known as a precursorof “hsa-miR-125a-3p”.

The term “hsa-miR-204-3p gene” or “hsa-miR-204-3p” used herein includesthe hsa-miR-204-3p gene (miRBase Accession No. MIMAT0022693) describedin SEQ ID NO: 106, a homolog or an ortholog of a different organismspecies, and the like. The hsa-miR-204-3p gene can be obtained by amethod described in Lim L P et al., 2003, Science., Vol. 299, p. 1540.Also, “hsa-mir-204” (miRBase Accession No. MI0000284, SEQ ID NO: 228)having a hairpin-like structure is known as a precursor of“hsa-miR-204-3p”.

The term “hsa-miR-1469 gene” or “hsa-miR-1469” used herein includes thehsa-miR-1469 gene (miRBase Accession No. MIMAT0007347) described in SEQID NO: 107, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-1469 gene can be obtained by a methoddescribed in Kawaji H et al., 2008, BMC Genomics, Vol. 9, p. 157. Also,“hsa-mir-1469” (miRBase Accession No. MI0007074, SEQ ID NO: 229) havinga hairpin-like structure is known as a precursor of “hsa-miR-1469”.

The term “hsa-miR-575 gene” or “hsa-miR-575” used herein includes thehsa-miR-575 gene (miRBase Accession No. MIMAT0003240) described in SEQID NO: 108, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-575 gene can be obtained by a method describedin Cummins J M, 2006, Proc Natl Acad Sci, Vol. 103, p. 3687-3692. Also,“hsa-mir-575” (miRBase Accession No. MI0003582, SEQ ID NO: 230) having ahairpin-like structure is known as a precursor of “hsa-miR-575”.

The term “hsa-miR-150-3p gene” or “hsa-miR-150-3p” used herein includesthe hsa-miR-150-3p gene (miRBase Accession No. MIMAT0004610) describedin SEQ ID NO: 109, a homolog or an ortholog of a different organismspecies, and the like. The hsa-miR-150-3p gene can be obtained by amethod described in Lagos-Quintana M et al., 2002, Curr Biol., Vol. 12,p. 735-739. Also, “hsa-mir-150” (miRBase Accession No. MI0000479, SEQ IDNO: 231) having a hairpin-like structure is known as a precursor of“hsa-miR-150-3p”.

The term “hsa-miR-423-5p gene” or “hsa-miR-423-5p” used herein includesthe hsa-miR-423-5p gene (miRBase Accession No. MIMAT0004748) describedin SEQ ID NO: 110, a homolog or an ortholog of a different organismspecies, and the like. The hsa-miR-423-5p gene can be obtained by amethod described in Kasashima K et al., 2004, Biochem Biophys ResCommun., Vol. 322, p. 403-410. Also, “hsa-mir-423” (miRBase AccessionNo. MI0001445, SEQ ID NO: 232) having a hairpin-like structure is knownas a precursor of “hsa-miR-423-5p”.

The term “hsa-miR-564 gene” or “hsa-miR-564” used herein includes thehsa-miR-564 gene (miRBase Accession No. MIMAT0003228) described in SEQID NO: 111, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-564 gene can be obtained by a method describedin Cummins J M, 2006, Proc Natl Acad Sci, Vol. 103, p. 3687-3692. Also,“hsa-mir-564” (miRBase Accession No. MI0003570, SEQ ID NO: 233) having ahairpin-like structure is known as a precursor of “hsa-miR-564”.

The term “hsa-miR-3188 gene” or “hsa-miR-3188” used herein includes thehsa-miR-3188 gene (miRBase Accession No. MIMAT0015070) described in SEQID NO: 112, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-3188 gene can be obtained by a methoddescribed in Stark M S et al., 2010, PLoS One., Vol. 5, e9685. Also,“hsa-mir-3188” (miRBase Accession No. MI0014232, SEQ ID NO: 234) havinga hairpin-like structure is known as a precursor of “hsa-miR-3188”.

The term “hsa-miR-1246 gene” or “hsa-miR-1246” used herein includes thehsa-miR-1246 gene (miRBase Accession No. MIMAT0005898) described in SEQID NO: 113, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-1246 gene can be obtained by a methoddescribed in Morin R D et al., 2008, Genome Res., Vol. 18, p. 610-621.Also, “hsa-mir-1246” (miRBase Accession No. MI0006381, SEQ ID NO: 235)having a hairpin-like structure is known as a precursor of“hsa-miR-1246”.

The term “hsa-miR-602 gene” or “hsa-miR-602” used herein includes thehsa-miR-602 gene (miRBase Accession No. MIMAT0003270) described in SEQID NO: 114, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-602 gene can be obtained by a method describedin Cummins J M, 2006, Proc Natl Acad Sci, Vol. 103, p. 3687-3692. Also,“hsa-mir-602” (miRBase Accession No. MI0003615, SEQ ID NO: 236) having ahairpin-like structure is known as a precursor of “hsa-miR-602”.

The term “hsa-miR-1290 gene” or “hsa-miR-1290” used herein includes thehsa-miR-1290 gene (miRBase Accession No. MIMAT0005880) described in SEQID NO: 115, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-1290 gene can be obtained by a methoddescribed in Morin R D et al., 2008, Genome Res., Vol. 18, p. 610-621.Also, “hsa-mir-1290” (miRBase Accession No. MI0006352, SEQ ID NO: 237)having a hairpin-like structure is known as a precursor of“hsa-miR-1290”.

The term “hsa-miR-16-5p gene” or “hsa-miR-16-5p” used herein includesthe hsa-miR-16-5p gene (miRBase Accession No. MIMAT0000069) described inSEQ ID NO: 116, a homolog or an ortholog of a different organismspecies, and the like. The hsa-miR-16-5p gene can be obtained by amethod described in Lagos-Quintana M et al., 2002, Curr Biol., Vol. 12,p. 735-739. Also, “hsa-mir-16-1 and hsa-mir-16-2” (miRBase AccessionNos. MI0000070 and MI0000115, SEQ ID NOs: 238 and 239) having ahairpin-like structure are known as precursors of “hsa-miR-16-5p”.

The term “hsa-miR-451a gene” or “hsa-miR-451a” used herein includes thehsa-miR-451a gene (miRBase Accession No. MIMAT0001631) described in SEQID NO: 117, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-451a gene can be obtained by a methoddescribed in Altuvia Y et al., 2005, Nucleic Acids Res., Vol. 33, p.2697-2706. Also, “hsa-mir-451a” (miRBase Accession No. MI0001729, SEQ IDNO: 240) having a hairpin-like structure are known as precursors of“hsa-miR-451a”.

The term “hsa-miR-24-3p gene” or “hsa-miR-24-3p” used herein includesthe hsa-miR-24-3p gene (miRBase Accession No. MIMAT0000080) described inSEQ ID NO: 118, a homolog or an ortholog of a different organismspecies, and the like. The hsa-miR-24-3p gene can be obtained by amethod described in Lagos-Quintana M et al., 2001, Science., Vol. 294,p. 853-858. Also, “hsa-mir-24-1 and hsa-mir-24-2” (miRBase AccessionNos. MI0000080 and MI0000081, SEQ ID NOs: 241 and 242) having ahairpin-like structure are known as precursors of “hsa-miR-24-3p”.

The term “hsa-miR-187-5p gene” or “hsa-miR-187-5p” used herein includesthe hsa-miR-187-5p gene (miRBase Accession No. MIMAT0004561) describedin SEQ ID NO: 119, a homolog or an ortholog of a different organismspecies, and the like. The hsa-miR-187-5p gene can be obtained by amethod described in Lim L P et al., 2003, Science., Vol. 299, p. 1540.Also, “hsa-mir-187” (miRBase Accession No. MI0000274, SEQ ID NO: 243)having a hairpin-like structure are known as precursors of“hsa-miR-187-5p”.

The term “hsa-miR-1908-5p gene” or “hsa-miR-1908-5p” used hereinincludes the hsa-miR-1908-5p gene (miRBase Accession No. MIMAT0007881)described in SEQ ID NO: 120, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-1908-5p gene can be obtainedby a method described in Bar M et al., 2008, Stem Cells., Vol. 26, p.2496-2505. Also, “hsa-mir-1908” (miRBase Accession No. MI0008329, SEQ IDNO: 244) having a hairpin-like structure are known as precursors of“hsa-miR-1908-5p”.

The term “hsa-miR-371a-5p gene” or “hsa-miR-371a-5p” used hereinincludes the hsa-miR-371a-5p gene (miRBase Accession No. MIMAT0004687)described in SEQ ID NO: 121, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-371a-5p gene can be obtainedby a method described in Suh M R et al., 2004, Dev Biol., Vol. 270, p.488-498. Also, “hsa-mir-371a” (miRBase Accession No. MI0000779, SEQ IDNO: 245) having a hairpin-like structure are known as precursors of“hsa-miR-371a-5p”.

The term “hsa-miR-550a-5p gene” or “hsa-miR-550a-5p” used hereinincludes the hsa-miR-550a-5p gene (miRBase Accession No. MIMAT0004800)described in SEQ ID NO: 122, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-550a-5p gene can be obtainedby a method described in Cummins J M, 2006, Proc Natl Acad Sci, Vol.103, p. 3687-3692. Also, “hsa-mir-550a-1 and hsa-mir-550a-2” (miRBaseAccession Nos. MI0003600 and MI0003601, SEQ ID NOs: 246 and 247) havinga hairpin-like structure are known as precursors of “hsa-miR-550a-5p”.

The term “hsa-miR-4417 gene” or “hsa-miR-4417” used herein includes thehsa-miR-4417 gene (miRBase Accession No. MIMAT0018929) described in SEQID NO: 349, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-4417 gene can be obtained by a methoddescribed in Jima D D et al., 2010, Blood, Vol. 116, e118-e127. Also,“hsa-mir-4417” (miRBase Accession No. MI0016753, SEQ ID NO: 384) havinga hairpin-like structure are known as precursors of “hsa-miR-4417”.

The term “hsa-miR-4707-5p gene” or “hsa-miR-4707-5p” used hereinincludes the hsa-miR-4707-5p gene (miRBase Accession No. MIMAT0019807)described in SEQ ID NO: 350, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-4707-5p gene can be obtainedby a method described in Persson H et al., 2011, Cancer Res, Vol. 71, p.78-86. Also, “hsa-mir-4707” (miRBase Accession No. MI0017340, SEQ ID NO:385) having a hairpin-like structure are known as precursors of“hsa-miR-4707-5p”.

The term “hsa-miR-7847-3p gene” or “hsa-miR-7847-3p” used hereinincludes the hsa-miR-7847-3p gene (miRBase Accession No. MIMAT0030422)described in SEQ ID NO: 351, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-7847-3p gene can be obtainedby a method described in Ple H et al., 2012, PLoS One, Vol. 7, e50746.Also, “hsa-mir-7847” (miRBase Accession No. MI0025517, SEQ ID NO: 386)having a hairpin-like structure are known as precursors of“hsa-miR-7847-3p”.

The term “hsa-miR-2861 gene” or “hsa-miR-2861” used herein includes thehsa-miR-2861 gene (miRBase Accession No. MIMAT0013802) described in SEQID NO: 352, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-2861 gene can be obtained by a methoddescribed in Li H et al., 2009, J Clin Invest, Vol. 119, p. 3666-3677.Also, “hsa-mir-2861” (miRBase Accession No. MI0013006, SEQ ID NO: 387)having a hairpin-like structure are known as precursors of“hsa-miR-2861”.

The term “hsa-miR-4513 gene” or “hsa-miR-4513” used herein includes thehsa-miR-4513 gene (miRBase Accession No. MIMAT0019050) described in SEQID NO: 353, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-4513 gene can be obtained by a methoddescribed in Jima D D et al., 2010, Blood, Vol. 116, e118-e127. Also,“hsa-mir-4513” (miRBase Accession No. MI0016879, SEQ ID NO: 388) havinga hairpin-like structure are known as precursors of “hsa-miR-4513”.

The term “hsa-miR-7111-5p gene” or “hsa-miR-7111-5p” used hereinincludes the hsa-miR-7111-5p gene (miRBase Accession No. MIMAT0028119)described in SEQ ID NO: 354, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-7111-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p.1634-1645. Also, “hsa-mir-7111” (miRBase Accession No. MI0022962, SEQ IDNO: 389) having a hairpin-like structure are known as precursors of“hsa-miR-7111-5p”.

The term “hsa-miR-6777-5p gene” or “hsa-miR-6777-5p” used hereinincludes the hsa-miR-6777-5p gene (miRBase Accession No. MIMAT0027454)described in SEQ ID NO: 355, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6777-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p.1634-1645. Also, “hsa-mir-6777” (miRBase Accession No. MI0022622, SEQ IDNO: 390) having a hairpin-like structure are known as precursors of“hsa-miR-6777-5p”.

The term “hsa-miR-7113-3p gene” or “hsa-miR-7113-3p” used hereinincludes the hsa-miR-7113-3p gene (miRBase Accession No. MIMAT0028124)described in SEQ ID NO: 356, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-7113-3p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p.1634-1645. Also, “hsa-mir-7113” (miRBase Accession No. MI0022964, SEQ IDNO: 391) having a hairpin-like structure are known as precursors of“hsa-miR-7113-3p”.

The term “hsa-miR-4648 gene” or “hsa-miR-4648” used herein includes thehsa-miR-4648 gene (miRBase Accession No. MIMAT0019710) described in SEQID NO: 357, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-4648 gene can be obtained by a methoddescribed in Persson H et al., 2011, Cancer Res, Vol. 71, p. 78-86.Also, “hsa-mir-4648” (miRBase Accession No. MI0017275, SEQ ID NO: 392)having a hairpin-like structure are known as precursors of“hsa-miR-4648”.

The term “hsa-miR-3184-5p gene” or “hsa-miR-3184-5p” used hereinincludes the hsa-miR-3184-5p gene (miRBase Accession No. MIMAT0015064)described in SEQ ID NO: 358, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-3184-5p gene can be obtainedby a method described in Stark M S et al., 2010, PLoS One, Vol. 5,e9685. Also, “hsa-mir-3184” (miRBase Accession No. MI0014226, SEQ ID NO:393) having a hairpin-like structure are known as precursors of“hsa-miR-3184-5p”.

The term “hsa-miR-4271 gene” or “hsa-miR-4271” used herein includes thehsa-miR-4271 gene (miRBase Accession No. MIMAT0016901) described in SEQID NO: 359, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-4271 gene can be obtained by a methoddescribed in Goff L A et al., 2009, PLoS One, Vol. 4, e7192. Also,“hsa-mir-4271” (miRBase Accession No. MI0015879, SEQ ID NO: 394) havinga hairpin-like structure are known as precursors of “hsa-miR-4271”.

The term “hsa-miR-6791-5p gene” or “hsa-miR-6791-5p” used hereinincludes the hsa-miR-6791-5p gene (miRBase Accession No. MIMAT0027482)described in SEQ ID NO: 360, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6791-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p.1634-1645. Also, “hsa-mir-6791” (miRBase Accession No. MI0022636, SEQ IDNO: 395) having a hairpin-like structure are known as precursors of“hsa-miR-6791-5p”.

The term “hsa-miR-642a-3p gene” or “hsa-miR-642a-3p” used hereinincludes the hsa-miR-642a-3p gene (miRBase Accession No. MIMAT0020924)described in SEQ ID NO: 361, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-642a-3p gene can be obtainedby a method described in Cummins J M et al., 2006, Proc Natl Acad SciUSA, Vol. 103, p. 3687-3692, Landgraf P et al., 2007, Cell, Vol. 129, p.1401-1414, Zaragosi L E et al., 2011, Genome Biol, Vol. 12, R64, etc.Also, “hsa-mir-642a” (miRBase Accession No. MI0003657, SEQ ID NO: 396)having a hairpin-like structure is known as a precursor of“hsa-miR-642a-3p”.

The term “hsa-miR-7108-5p gene” or “hsa-miR-7108-5p” used hereinincludes the hsa-miR-7108-5p gene (miRBase Accession No. MIMAT0028113)described in SEQ ID NO: 362, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-7108-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p.1634-1645. Also, “hsa-mir-7108” (miRBase Accession No. MI0022959, SEQ IDNO: 397) having a hairpin-like structure is known as a precursor of“hsa-miR-7108-5p”.

The term “hsa-miR-128-1-5p gene” or “hsa-miR-128-1-5p” used hereinincludes the hsa-miR-128-1-5p gene (miRBase Accession No. MIMAT0026477)described in SEQ ID NO: 363, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-128-1-5p gene can beobtained by a method described in Lagos-Quintana M et al., 2002, CurrBiol, Vol. 12, p. 735-739, Kasashima K et al., 2004, Biochem Biophys ResCommun, Vol. 322, p. 403-410, Landgraf P et al., 2007, Cell, Vol. 129,p. 1401-1414, Meunier J et al., 2013, Genome Res, Vol. 23, p. 34-45,etc. Also, “hsa-mir-128-1” (miRBase Accession No. MI0000447, SEQ ID NO:398) having a hairpin-like structure is known as a precursor of“hsa-miR-128-1-5p”.

The term “hsa-miR-5196-5p gene” or “hsa-miR-5196-5p” used hereinincludes the hsa-miR-5196-5p gene (miRBase Accession No. MIMAT0021128)described in SEQ ID NO: 364, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-5196-5p gene can be obtainedby a method described in Schotte D et al., 2011, Leukemia, Vol. 25, p.1389-1399. Also, “hsa-mir-5196” (miRBase Accession No. MI0018175, SEQ IDNO: 399) having a hairpin-like structure is known as a precursor of“hsa-miR-5196-5p”.

The term “hsa-miR-3178 gene” or “hsa-miR-3178” used herein includes thehsa-miR-3178 gene (miRBase Accession No. MIMAT0015055) described in SEQID NO: 365, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-3178 gene can be obtained by a methoddescribed in Stark M S et al., 2010, PLoS One, Vol. 5, e9685. Also,“hsa-mir-3178” (miRBase Accession No. MI0014212, SEQ ID NO: 400) havinga hairpin-like structure is known as a precursor of “hsa-miR-3178”.

The term “hsa-miR-3656 gene” or “hsa-miR-3656” used herein includes thehsa-miR-3656 gene (miRBase Accession No. MIMAT0018076) described in SEQID NO: 366, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-3656 gene can be obtained by a methoddescribed in Meiri E et al., 2010, Nucleic Acids Res, Vol. 38, p.6234-6246. Also, “hsa-mir-3656” (miRBase Accession No. MI0016056, SEQ IDNO: 401) having a hairpin-like structure is known as a precursor of“hsa-miR-3656”.

The term “hsa-miR-92a-2-5p gene” or “hsa-miR-92a-2-5p” used hereinincludes the hsa-miR-92a-2-5p gene (miRBase Accession No. MIMAT0004508)described in SEQ ID NO: 367, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-92a-2-5p gene can beobtained by a method described in Mourelatos Z et al., 2002, Genes Dev,Vol. 16, p. 720-728, Dostie J et al., 2003, RNA, Vol. 9, p. 180-186,Houbaviy H B et al., 2003, Dev Cell, Vol. 5, p. 351-358, Suh M R et al.,2004, Dev Biol, Vol. 270, p. 488-498, Kasashima K et al., 2004, BiochemBiophys Res Commun, Vol. 322, p. 403-410, Fu H et al., 2005, FEBS Lett,Vol. 579, p. 3849-3854, Landgraf P et al., 2007, Cell, Vol. 129, p.1401-1414, Lui W O et al., 2007, Cancer Res, Vol. 67, p. 6031-6043, etc.Also, “hsa-mir-92a-2” (miRBase Accession No. MI0000094, SEQ ID NO: 402)having a hairpin-like structure is known as a precursor of“hsa-miR-92a-2-5p”.

The term “hsa-miR-6769b-5p gene” or “hsa-miR-6769b-5p” used hereinincludes the hsa-miR-6769b-5p gene (miRBase Accession No. MIMAT0027620)described in SEQ ID NO: 368, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6769b-5p gene can beobtained by a method described in Ladewig E et al., 2012, Genome Res,Vol. 22, p. 1634-1645. Also, “hsa-mir-6769b” (miRBase Accession No.MI0022706, SEQ ID NO: 403) having a hairpin-like structure is known as aprecursor of “hsa-miR-6769b-5p”.

The term “hsa-miR-4689 gene” or “hsa-miR-4689” used herein includes thehsa-miR-4689 gene (miRBase Accession No. MIMAT0019778) described in SEQID NO: 369, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-4689 gene can be obtained by a methoddescribed in Persson H et al., 2011, Cancer Res, Vol. 71, p. 78-86.Also, “hsa-mir-4689” (miRBase Accession No. MI0017322, SEQ ID NO: 404)having a hairpin-like structure is known as a precursor of“hsa-miR-4689”.

The term “hsa-miR-6076 gene” or “hsa-miR-6076” used herein includes thehsa-miR-6076 gene (miRBase Accession No. MIMAT0023701) described in SEQID NO: 370, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-6076 gene can be obtained by a methoddescribed in Voellenkle C et al., 2012, RNA, Vol. 18, p. 472-484. Also,“hsa-mir-6076” (miRBase Accession No. MI0020353, SEQ ID NO: 405) havinga hairpin-like structure is known as a precursor of “hsa-miR-6076”.

The term “hsa-miR-92b-5p gene” or “hsa-miR-92b-5p” used herein includesthe hsa-miR-92b-5p gene (miRBase Accession No. MIMAT0004792) describedin SEQ ID NO: 371, a homolog or an ortholog of a different organismspecies, and the like. The hsa-miR-92b-5p gene can be obtained by amethod described in Cummins J M et al., 2006, Proc Natl Acad Sci USA,Vol. 103, p. 3687-3692, Landgraf P et al., 2007, Cell, Vol. 129, p.1401-1414, Lui W O et al., 2007, Cancer Res, Vol. 67, p. 6031-6043, etc.Also, “hsa-mir-92b” (miRBase Accession No. MI0003560, SEQ ID NO: 406)having a hairpin-like structure is known as a precursor of“hsa-miR-92b-5p”.

The term “hsa-miR-6774-5p gene” or “hsa-miR-6774-5p” used hereinincludes the hsa-miR-6774-5p gene (miRBase Accession No. MIMAT0027448)described in SEQ ID NO: 372, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6774-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p.1634-1645. Also, “hsa-mir-6774” (miRBase Accession No. MI0022619, SEQ IDNO: 407) having a hairpin-like structure is known as a precursor of“hsa-miR-6774-5p”.

The term “hsa-miR-486-3p gene” or “hsa-miR-486-3p” used herein includesthe hsa-miR-486-3p gene (miRBase Accession No. MIMAT0004762) describedin SEQ ID NO: 373, a homolog or an ortholog of a different organismspecies, and the like. The hsa-miR-486-3p gene can be obtained by amethod described in Fu H et al., 2005, FEBS Lett, Vol. 579, p.3849-3854, Landgraf P et al., 2007, Cell, Vol. 129, p. 1401-1414,Meunier J et al., 2013, Genome Res, Vol. 23, p. 34-45, etc. Also,“hsa-mir-486 and hsa-mir-486-2” (miRBase Accession Nos. MI0002470 andMI0023622, SEQ ID NOs: 408 and 409) having a hairpin-like structure areknown as precursors of “hsa-miR-486-3p”.

The term “hsa-miR-6806-5p gene” or “hsa-miR-6806-5p” used hereinincludes the hsa-miR-6806-5p gene (miRBase Accession No. MIMAT0027512)described in SEQ ID NO: 374, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6806-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p.1634-1645. Also, “hsa-mir-6806” (miRBase Accession No. MI0022651, SEQ IDNO: 410) having a hairpin-like structure is known as a precursor of“hsa-miR-6806-5p”.

The term “hsa-miR-6842-5p gene” or “hsa-miR-6842-5p” used hereinincludes the hsa-miR-6842-5p gene (miRBase Accession No. MIMAT0027586)described in SEQ ID NO: 375, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6842-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p.1634-1645. Also, “hsa-mir-6842” (miRBase Accession No. MI0022688, SEQ IDNO: 411) having a hairpin-like structure is known as a precursor of“hsa-miR-6842-5p”.

The term “hsa-miR-6716-5p gene” or “hsa-miR-6716-5p” used hereinincludes the hsa-miR-6716-5p gene (miRBase Accession No. MIMAT0025844)described in SEQ ID NO: 376, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6716-5p gene can be obtainedby a method described in Li Y et al., 2012, Gene, Vol. 497, p. 330-335.Also, “hsa-mir-6716” (miRBase Accession No. MI0022550, SEQ ID NO: 412)having a hairpin-like structure is known as a precursor of“hsa-miR-6716-5p”.

The term “hsa-miR-557 gene” or “hsa-miR-557” used herein includes thehsa-miR-557 gene (miRBase Accession No. MIMAT0003221) described in SEQID NO: 377, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-557 gene can be obtained by a method describedin Cummins J M et al., 2006, Proc Natl Acad Sci USA, Vol. 103, p.3687-3692. Also, “hsa-mir-557” (miRBase Accession No. MI0003563, SEQ IDNO: 413) having a hairpin-like structure is known as a precursor of“hsa-miR-557”.

The term “hsa-miR-4673 gene” or “hsa-miR-4673” used herein includes thehsa-miR-4673 gene (miRBase Accession No. MIMAT0019755) described in SEQID NO: 378, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-4673 gene can be obtained by a methoddescribed in Persson H et al., 2011, Cancer Res, Vol. 71, p. 78-86.Also, “hsa-mir-4673” (miRBase Accession No. MI0017304, SEQ ID NO: 414)having a hairpin-like structure is known as a precursor of“hsa-miR-4673”.

The term “hsa-miR-4674 gene” or “hsa-miR-4674” used herein includes thehsa-miR-4674 gene (miRBase Accession No. MIMAT0019756) described in SEQID NO: 379, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-4674 gene can be obtained by a methoddescribed in Persson H et al., 2011, Cancer Res, Vol. 71, p. 78-86.Also, “hsa-mir-4674” (miRBase Accession No. MI0017305, SEQ ID NO: 415)having a hairpin-like structure is known as a precursor of“hsa-miR-4674”.

The term “hsa-miR-4442 gene” or “hsa-miR-4442” used herein includes thehsa-miR-4442 gene (miRBase Accession No. MIMAT0018960) described in SEQID NO: 380, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-4442 gene can be obtained by a methoddescribed in Jima D D et al., 2010, Blood, Vol. 116, e118-e127. Also,“hsa-mir-4442” (miRBase Accession No. MI0016785, SEQ ID NO: 416) havinga hairpin-like structure is known as a precursor of “hsa-miR-4442”.

The term “hsa-miR-1915-3p gene” or “hsa-miR-1915-3p” used hereinincludes the hsa-miR-1915-3p gene (miRBase Accession No. MIMAT0007892)described in SEQ ID NO: 381, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-1915-3p gene can be obtainedby a method described in Bar M et al., 2008, Stem Cells, Vol. 26, p.2496-2505. Also, “hsa-mir-1915” (miRBase Accession No. MI0008336, SEQ IDNO: 417) having a hairpin-like structure is known as a precursor of“hsa-miR-1915-3p”.

The term “hsa-miR-4687-3p gene” or “hsa-miR-4687-3p” used hereinincludes the hsa-miR-4687-3p gene (miRBase Accession No. MIMAT0019775)described in SEQ ID NO: 382, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-4687-3p gene can be obtainedby a method described in Persson H et al., 2011, Cancer Res, Vol. 71, p.78-86. Also, “hsa-mir-4687” (miRBase Accession No. MI0017319, SEQ ID NO:418) having a hairpin-like structure is known as a precursor of“hsa-miR-4687-3p”.

The term “hsa-miR-92b-3p gene” or “hsa-miR-92b-3p” used herein includesthe hsa-miR-92b-3p gene (miRBase Accession No. MIMAT0003218) describedin SEQ ID NO: 383, a homolog or an ortholog of a different organismspecies, and the like. The hsa-miR-92b-3p gene can be obtained by amethod described in Cummins J M et al., 2006, Proc Natl Acad Sci USA,Vol. 103, p. 3687-3692, Landgraf P et al., 2007, Cell, Vol. 129, p.1401-1414, Lui W O et al., 2007, Cancer Res, Vol. 67, p. 6031-6043.Also, “hsa-mir-92b” (miRBase Accession No. MI0003560, SEQ ID NO: 419)having a hairpin-like structure is known as a precursor of“hsa-miR-92b-3p”.

The term “hsa-miR-1203 gene” or “hsa-miR-1203” used herein includes thehsa-miR-1203 gene (miRBase Accession No. MIMAT0005866) described in SEQID NO: 464, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-1203 gene can be obtained by a methoddescribed in Marton S et al., 2008, Leukemia., Vol. 22, p. 330-338.Also, “hsa-mir-1203” (miRBase Accession No. MI0006335, SEQ ID NO: 467)having a hairpin-like structure is known as a precursor of“hsa-miR-1203”.

The term “hsa-miR-663b gene” or “hsa-miR-663b” used herein includes thehsa-miR-663b gene (miRBase Accession No. MIMAT0005867) described in SEQID NO: 465, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-663b gene can be obtained by a methoddescribed in Takada S et al., 2008, Leukemia., Vol. 22, p. 1274-1278.Also, “hsa-mir-663b” (miRBase Accession No. MI0006336, SEQ ID NO: 475)having a hairpin-like structure is known as a precursor of“hsa-miR-663b”.

The term “hsa-miR-4258 gene” or “hsa-miR-4258” used herein includes thehsa-miR-4258 gene (miRBase Accession No. MIMAT0016879) described in SEQID NO: 466, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-4258 gene can be obtained by a methoddescribed in Goff L A et al., 2009, PLoS One., Vol. 4, e7192. Also,“hsa-mir-4258” (miRBase Accession No. MI0015857, SEQ ID NO: 476) havinga hairpin-like structure is known as a precursor of “hsa-miR-4258”.

The term “hsa-miR-4649-5p gene” or “hsa-miR-4649-5p” used hereinincludes the hsa-miR-4649-5p gene (miRBase Accession No. MIMAT0019711)described in SEQ ID NO: 467, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-4649-5p gene can be obtainedby a method described in Persson H et al., 2011, Cancer Res., Vol. 71,p. 78-86. Also, “hsa-mir-4649” (miRBase Accession No. MI0017276, SEQ IDNO: 477) having a hairpin-like structure is known as a precursor of“hsa-miR-4649-5p”.

The term “hsa-miR-4516 gene” or “hsa-miR-4516” used herein includes thehsa-miR-4516 gene (miRBase Accession No. MIMAT0019053) described in SEQID NO: 468, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-4516 gene can be obtained by a methoddescribed in Jima D D et al., 2010, Blood., Vol. 116, e118-e127. Also,“hsa-mir-4516” (miRBase Accession No. MI0016882, SEQ ID NO: 478) havinga hairpin-like structure is known as a precursor of “hsa-miR-4516”.

The term “hsa-miR-3619-3p gene” or “hsa-miR-3619-3p” used hereinincludes the hsa-miR-3619-3p gene (miRBase Accession No. MIMAT0019219)described in SEQ ID NO: 469, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-3619-3p gene can be obtainedby a method described in Witten D et al., 2010, BMC Biol., Vol. 8, p.58. Also, “hsa-mir-3619” (miRBase Accession No. MI0016009, SEQ ID NO:479) having a hairpin-like structure is known as a precursor of“hsa-miR-3619-3p”.

The term “hsa-miR-6826-5p gene” or “hsa-miR-6826-5p” used hereinincludes the hsa-miR-6826-5p gene (miRBase Accession No. MIMAT0027552)described in SEQ ID NO: 470, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6826-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6826” (miRBase Accession No. MI0022671, SEQID NO: 480) having a hairpin-like structure is known as a precursor of“hsa-miR-6826-5p”.

The term “hsa-miR-6757-5p gene” or “hsa-miR-6757-5p” used hereinincludes the hsa-miR-6757-5p gene (miRBase Accession No. MIMAT0027414)described in SEQ ID NO: 471, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6757-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res., Vol. 22,p. 1634-1645. Also, “hsa-mir-6757” (miRBase Accession No. MI0022602, SEQID NO: 481) having a hairpin-like structure is known as a precursor of“hsa-miR-6757-5p”.

The term “hsa-miR-3131 gene” or “hsa-miR-3131” used herein includes thehsa-miR-3131 gene (miRBase Accession No. MIMAT0014996) described in SEQID NO: 472, a homolog or an ortholog of a different organism species,and the like. The hsa-miR-3131 gene can be obtained by a methoddescribed in Stark M S et al., 2010, PLoS One., Vol. 5, e9685. Also,“hsa-mir-3131” (miRBase Accession No. MI0014151, SEQ ID NO: 482) havinga hairpin-like structure is known as a precursor of “hsa-miR-3131”.

The term “hsa-miR-1343-3p gene” or “hsa-miR-1343-3p” used hereinincludes the hsa-miR-1343-3p gene (miRBase Accession No. MIMAT0019776)described in SEQ ID NO: 473, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-1343-3p gene can be obtainedby a method described in Persson H et al., 2011, Cancer Res., Vol. 71,p. 78-86. Also, “hsa-mir-1343” (miRBase Accession No. MI0017320, SEQ IDNO: 483) having a hairpin-like structure is known as a precursor of“hsa-miR-1343-3p”.

The term “hsa-miR-6775-5p gene” or “hsa-miR-6775-5p” used hereinincludes the hsa-miR-6775-5p gene (miRBase Accession No. MIMAT0027450)described in SEQ ID NO: 492, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6775-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p.1634-1645. Also, “hsa-mir-6775” (miRBase Accession No. MI0022620, SEQ IDNO: 495) having a hairpin-like structure is known as a precursor of“hsa-miR-6775-5p”.

The term “hsa-miR-6813-5p gene” or “hsa-miR-6813-5p” used hereinincludes the hsa-miR-6813-5p gene (miRBase Accession No. MIMAT0027526)described in SEQ ID NO: 493, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-6813-5p gene can be obtainedby a method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p.1634-1645. Also, “hsa-mir-6813” (miRBase Accession No. MI0022658, SEQ IDNO: 496) having a hairpin-like structure is known as a precursor of“hsa-miR-6813-5p”.

The term “hsa-miR-3940-5p gene” or “hsa-miR-3940-5p” used hereinincludes the hsa-miR-3940-5p gene (miRBase Accession No. MIMAT0019229)described in SEQ ID NO: 494, a homolog or an ortholog of a differentorganism species, and the like. The hsa-miR-3940-5p gene can be obtainedby a method described in Liao J Y et al., 2010, PLoS One, Vol. 5,e10563. Also, “hsa-mir-3940” (miRBase Accession No. MI0016597, SEQ IDNO: 497) having a hairpin-like structure is known as a precursor of“hsa-miR-3940-5p”.

A mature miRNA may become a variant due to the sequence cleaved shorteror longer by one to several flanking nucleotides, or due to substitutionof nucleotides, when cut out as the mature miRNA from its RNA precursorhaving a hairpin-like structure. This variant is called isomiR (Morin RD. et al., 2008, Genome Res., Vol. 18, p. 610-621). The miRBase Release20 shows the nucleotide sequences represented by SEQ ID NOs: 1 to 122,349 to 383, 464 to 473, and 492 to 494 as well as a large number of thenucleotide sequence variants and fragments represented by SEQ ID NOs:248 to 348, 420 to 463, 484 to 491, and 498 to 499, called isomiRs.These variants can also be obtained as miRNAs having a nucleotidesequence represented by any of SEQ ID NOs: 1 to 122, 349 to 383, 464 to473, and 492 to 494. Specifically, among the variants of polynucleotidesconsisting of the nucleotide sequence represented by any of SEQ ID NOs:6, 10, 12, 13, 15, 18, 19, 23, 30, 33, 34, 41, 43, 46, 48, 51, 55, 59,60, 62, 63, 64, 66, 68, 71, 74, 80, 83, 86, 87, 89, 90, 92, 95, 99, 100,101, 105, 106, 109, 110, 112, 113, 115, 116, 117, 118, 119, 121, 349,350, 352, 353, 357, 359, 361, 363, 364, 365, 366, 367, 369, 371, 373,376, 378, 379, 380, 381, 382, 383, 465, 468, 472, 473, and 492 or anucleotide sequence derived from the nucleotide sequence by thereplacement of u with t according to the present invention, examples ofthe longest variants registered in miRBase Release 20 includepolynucleotides represented by SEQ ID NOs: 248, 250, 251, 253, 255, 257,259, 262, 265, 267, 268, 272, 275, 277, 278, 279, 282, 285, 287, 289,291, 292, 294, 296, 298, 300, 302, 305, 306, 307, 309, 310, 312, 314,316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 337, 339, 341,342, 344, 346, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440,442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 484, 486, 488,490, and 498, respectively. Also, among the variants of polynucleotidesconsisting of a nucleotide sequence represented by any of SEQ ID NOs: 6,10, 12, 13, 15, 18, 19, 23, 30, 33, 34, 41, 43, 46, 48, 51, 55, 59, 60,62, 63, 64, 66, 68, 71, 74, 80, 83, 86, 87, 89, 90, 92, 95, 99, 100,101, 105, 106, 109, 110, 112, 113, 115, 116, 117, 118, 119, 121, 349,350, 352, 353, 357, 359, 361, 363, 364, 365, 366, 367, 369, 371, 373,376, 378, 379, 380, 381, 382, 383, 465, 468, 472, 473 and 492 or anucleotide sequence derived from the nucleotide sequence by thereplacement of u with t according to the present invention, examples ofshortest variants registered in the miRBase Release 20 includepolynucleotides having sequences represented by SEQ ID NOs: 249, 252,254, 256, 258, 260, 261, 263, 264, 266, 269, 270, 271, 273, 274, 276,280, 281, 283, 284, 286, 288, 290, 293, 295, 297, 299, 301, 303, 304,308, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335,338, 340, 343, 345, 347, 348, 421, 423, 425, 427, 429, 431, 433, 435,437, 439, 441, 443, 445, 447, 449, 451, 453, 455, 457, 459, 461, 463,485, 487, 489, 491, and 499, respectively. In addition to these variantsand fragments, examples thereof include a large number of isomiRpolynucleotides of SEQ ID NOs: 6, 10, 12, 13, 15, 18, 19, 23, 30, 33,34, 41, 43, 46, 48, 51, 55, 59, 60, 62, 63, 64, 66, 68, 71, 74, 80, 83,86, 87, 89, 90, 92, 95, 99, 100, 101, 105, 106, 109, 110, 112, 113, 115,116, 117, 118, 119, 121, 349, 350, 352, 353, 357, 359, 361, 363, 364,365, 366, 367, 369, 371, 373, 376, 378, 379, 380, 381, 382, 383, 465,468, 472, 473 and 492 registered in the miRBase. Examples of thepolynucleotide comprising a nucleotide sequence represented by any ofSEQ ID NOs: 1 to 122, 349 to 383, 464 to 473 and 492 to 494 include apolynucleotide represented by any of SEQ ID NOs: 123 to 247, 384 to 419,474 to 483, and 495 to 497, which are their respective precursors.

The names and miRBase Accession Nos. (registration numbers) of the genesrepresented by SEQ ID NOs: 1 to 499 are shown in Table 1.

As used herein, the term “capable of specifically binding” means thatthe nucleic acid probe or the primer used in the present invention bindsto a particular target nucleic acid and cannot substantially bind toother nucleic acids.

TABLE 1 miRBase SEQ ID NO: Gene name registration No. 1 hsa-miR-6893-5pMIMAT0027686 2 hsa-miR-6075 MIMAT0023700 3 hsa-miR-6820-5p MIMAT00275404 hsa-miR-4294 MIMAT0016849 5 hsa-miR-6729-5p MIMAT0027359 6hsa-miR-4476 MIMAT0019003 7 hsa-miR-6836-3p MIMAT0027575 8hsa-miR-6765-3p MIMAT0027431 9 hsa-miR-6799-5p MIMAT0027498 10hsa-miR-4530 MIMAT0019069 11 hsa-miR-7641 MIMAT0029782 12 hsa-miR-4454MIMAT0018976 13 hsa-miR-615-5p MIMAT0004804 14 hsa-miR-8073 MIMAT003100015 hsa-miR-663a MIMAT0003326 16 hsa-miR-4634 MIMAT0019691 17hsa-miR-4450 MIMAT0018971 18 hsa-miR-4792 MIMAT0019964 19 hsa-miR-665MIMAT0004952 20 hsa-miR-7975 MIMAT0031178 21 hsa-miR-7109-5pMIMAT0028115 22 hsa-miR-6789-5p MIMAT0027478 23 hsa-miR-4497MIMAT0019032 24 hsa-miR-6877-5p MIMAT0027654 25 hsa-miR-6880-5pMIMAT0027660 26 hsa-miR-7977 MIMAT0031180 27 hsa-miR-4734 MIMAT001985928 hsa-miR-6821-5p MIMAT0027542 29 hsa-miR-8089 MIMAT0031016 30hsa-miR-5585-3p MIMAT0022286 31 hsa-miR-6085 MIMAT0023710 32hsa-miR-6845-5p MIMAT0027590 33 hsa-miR-4651 MIMAT0019715 34hsa-miR-4433-3p MIMAT0018949 35 hsa-miR-1231 MIMAT0005586 36hsa-miR-4665-5p MIMAT0019739 37 hsa-miR-7114-5p MIMAT0028125 38hsa-miR-1238-5p MIMAT0022947 39 hsa-miR-8069 MIMAT0030996 40hsa-miR-4732-5p MIMAT0019855 41 hsa-miR-619-5p MIMAT0026622 42hsa-miR-3622a-5p MIMAT0018003 43 hsa-miR-1260a MIMAT0005911 44hsa-miR-6741-5p MIMAT0027383 45 hsa-miR-6781-5p MIMAT0027462 46hsa-miR-6125 MIMAT0024598 47 hsa-miR-6805-5p MIMAT0027510 48hsa-miR-6132 MIMAT0024616 49 hsa-miR-6872-3p MIMAT0027645 50hsa-miR-6875-5p MIMAT0027650 51 hsa-miR-1908-3p MIMAT0026916 52hsa-miR-4433b-3p MIMAT0030414 53 hsa-miR-4736 MIMAT0019862 54hsa-miR-5100 MIMAT0022259 55 hsa-miR-6724-5p MIMAT0025856 56hsa-miR-7107-5p MIMAT0028111 57 hsa-miR-6726-5p MIMAT0027353 58hsa-miR-3185 MIMAT0015065 59 hsa-miR-4638-5p MIMAT0019695 60hsa-miR-1273g-3p MIMAT0022742 61 hsa-miR-6778-5p MIMAT0027456 62hsa-miR-328-5p MIMAT0026486 63 hsa-miR-3679-3p MIMAT0018105 64hsa-miR-1228-3p MIMAT0005583 65 hsa-miR-6779-5p MIMAT0027458 66hsa-miR-4723-5p MIMAT0019838 67 hsa-miR-6850-5p MIMAT0027600 68hsa-miR-760 MIMAT0004957 69 hsa-miR-7704 MIMAT0030019 70 hsa-miR-8072MIMAT0030999 71 hsa-miR-4486 MIMAT0019020 72 hsa-miR-1913 MIMAT000788873 hsa-miR-4656 MIMAT0019723 74 hsa-miR-1260b MIMAT0015041 75hsa-miR-7106-5p MIMAT0028109 76 hsa-miR-6889-5p MIMAT0027678 77hsa-miR-6780b-5p MIMAT0027572 78 hsa-miR-6090 MIMAT0023715 79hsa-miR-4534 MIMAT0019073 80 hsa-miR-4449 MIMAT0018968 81hsa-miR-5195-3p MIMAT0021127 82 hsa-miR-1202 MIMAT0005865 83hsa-miR-4467 MIMAT0018994 84 hsa-miR-6515-3p MIMAT0025487 85hsa-miR-4281 MIMAT0016907 86 hsa-miR-4505 MIMAT0019041 87 hsa-miR-4484MIMAT0019018 88 hsa-miR-6805-3p MIMAT0027511 89 hsa-miR-3135bMIMAT0018985 90 hsa-miR-3162-5p MIMAT0015036 91 hsa-miR-6768-5pMIMAT0027436 92 hsa-miR-6721-5p MIMAT0025852 93 hsa-miR-1227-5pMIMAT0022941 94 hsa-miR-6722-3p MIMAT0025854 95 hsa-miR-4286MIMAT0016916 96 hsa-miR-4746-3p MIMAT0019881 97 hsa-miR-6727-5pMIMAT0027355 98 hsa-miR-6816-5p MIMAT0027532 99 hsa-miR-4741MIMAT0019871 100 hsa-miR-4508 MIMAT0019045 101 hsa-miR-940 MIMAT0004983102 hsa-miR-4327 MIMAT0016889 103 hsa-miR-4665-3p MIMAT0019740 104hsa-miR-718 MIMAT0012735 105 hsa-miR-125a-3p MIMAT0004602 106hsa-miR-204-3p MIMAT0022693 107 hsa-miR-1469 MIMAT0007347 108hsa-miR-575 MIMAT0003240 109 hsa-miR-150-3p MIMAT0004610 110hsa-miR-423-5p MIMAT0004748 111 hsa-miR-564 MIMAT0003228 112hsa-miR-3188 MIMAT0015070 113 hsa-miR-1246 MIMAT0005898 114 hsa-miR-602MIMAT0003270 115 hsa-miR-1290 MIMAT0005880 116 hsa-miR-16-5pMIMAT0000069 117 hsa-miR-451a MIMAT0001631 118 hsa-miR-24-3pMIMAT0000080 119 hsa-miR-187-5p MIMAT0004561 120 hsa-miR-1908-5pMIMAT0007881 121 hsa-miR-371a-5p MIMAT0004687 122 hsa-miR-550a-5pMIMAT0004800 123 hsa-mir-6893 MI0022740 124 hsa-mir-6075 MI0020352 125hsa-mir-6820 MI0022665 126 hsa-mir-4294 MI0015827 127 hsa-mir-6729MI0022574 128 hsa-mir-4476 MI0016828 129 hsa-mir-6836 MI0022682 130hsa-mir-6765 MI0022610 131 hsa-mir-6799 MI0022644 132 hsa-mir-4530MI0016897 133 hsa-mir-7641-1 MI0024975 134 hsa-mir-7641-2 MI0024976 135hsa-mir-4454 MI0016800 136 hsa-mir-615 MI0003628 137 hsa-mir-8073MI0025909 138 hsa-mir-663a MI0003672 139 hsa-mir-4634 MI0017261 140hsa-mir-4450 MI0016795 141 hsa-mir-4792 MI0017439 142 hsa-mir-665MI0005563 143 hsa-mir-7975 MI0025751 144 hsa-mir-7109 MI0022960 145hsa-mir-6789 MI0022634 146 hsa-mir-4497 MI0016859 147 hsa-mir-6877MI0022724 148 hsa-mir-6880 MI0022727 149 hsa-mir-7977 MI0025753 150hsa-mir-4734 MI0017371 151 hsa-mir-6821 MI0022666 152 hsa-mir-8089MI0025925 153 hsa-mir-5585 MI0019142 154 hsa-mir-6085 MI0020362 155hsa-mir-6845 MI0022691 156 hsa-mir-4651 MI0017279 157 hsa-mir-4433MI0016773 158 hsa-mir-1231 MI0006321 159 hsa-mir-4665 MI0017295 160hsa-mir-7114 MI0022965 161 hsa-mir-1238 MI0006328 162 hsa-mir-8069MI0025905 163 hsa-mir-4732 MI0017369 164 hsa-mir-619 MI0003633 165hsa-mir-3622a MI0016013 166 hsa-mir-1260a MI0006394 167 hsa-mir-6741MI0022586 168 hsa-mir-6781 MI0022626 169 hsa-mir-6125 MI0021259 170hsa-mir-6805 MI0022650 171 hsa-mir-6132 MI0021277 172 hsa-mir-6872MI0022719 173 hsa-mir-6875 MI0022722 174 hsa-mir-1908 MI0008329 175hsa-mir-4433b MI0025511 176 hsa-mir-4736 MI0017373 177 hsa-mir-5100MI0019116 178 hsa-mir-6724 MI0022559 179 hsa-mir-7107 MI0022958 180hsa-mir-6726 MI0022571 181 hsa-mir-3185 MI0014227 182 hsa-mir-4638MI0017265 183 hsa-mir-1273g MI0018003 184 hsa-mir-6778 MI0022623 185hsa-mir-328 MI0000804 186 hsa-mir-3679 MI0016080 187 hsa-mir-1228MI0006318 188 hsa-mir-6779 MI0022624 189 hsa-mir-4723 MI0017359 190hsa-mir-6850 MI0022696 191 hsa-mir-760 MI0005567 192 hsa-mir-7704MI0025240 193 hsa-mir-8072 MI0025908 194 hsa-mir-4486 MI0016847 195hsa-mir-1913 MI0008334 196 hsa-mir-4656 MI0017284 197 hsa-mir-1260bMI0014197 198 hsa-mir-7106 MI0022957 199 hsa-mir-6889 MI0022736 200hsa-mir-6780b MI0022681 201 hsa-mir-6090 MI0020367 202 hsa-mir-4534MI0016901 203 hsa-mir-4449 MI0016792 204 hsa-mir-5195 MI0018174 205hsa-mir-1202 MI0006334 206 hsa-mir-4467 MI0016818 207 hsa-mir-6515MI0022227 208 hsa-mir-4281 MI0015885 209 hsa-mir-4505 MI0016868 210hsa-mir-4484 MI0016845 211 hsa-mir-6805 MI0022650 212 hsa-mir-3135bMI0016809 213 hsa-mir-3162 MI0014192 214 hsa-mir-6768 MI0022613 215hsa-mir-6721 MI0022556 216 hsa-mir-1227 MI0006316 217 hsa-mir-6722MI0022557 218 hsa-mir-4286 MI0015894 219 hsa-mir-4746 MI0017385 220hsa-mir-6727 MI0022572 221 hsa-mir-6816 MI0022661 222 hsa-mir-4741MI0017379 223 hsa-mir-4508 MI0016872 224 hsa-mir-940 MI0005762 225hsa-mir-4327 MI0015867 226 hsa-mir-718 MI0012489 227 hsa-mir-125aMI0000469 228 hsa-mir-204 MI0000284 229 hsa-mir-1469 MI0007074 230hsa-mir-575 MI0003582 231 hsa-mir-150 MI0000479 232 hsa-mir-423MI0001445 233 hsa-mir-564 MI0003570 234 hsa-mir-3188 MI0014232 235hsa-mir-1246 MI0006381 236 hsa-mir-602 MI0003615 237 hsa-mir-1290MI0006352 238 hsa-mir-16-1 MI0000070 239 hsa-mir-16-2 MI0000115 240hsa-mir-451a MI0001729 241 hsa-mir-24-1 MI0000080 242 hsa-mir-24-2MI0000081 243 hsa-mir-187 MI0000274 244 hsa-mir-1908 MI0008329 245hsa-mir-371a MI0000779 246 hsa-mir-550a-1 MI0003600 247 hsa-mir-550a-2MI0003601 248 isomiR example 1 of SEQ ID NO: 6 — 249 isomiR example 2 ofSEQ ID NO: 6 — 250 isomiR example 1 of SEQ ID NO: 10 — 251 isomiRexample 1 of SEQ ID NO: 12 — 252 isomiR example 2 of SEQ ID NO: 12 — 253isomiR example 1 of SEQ ID NO: 13 — 254 isomiR example 2 of SEQ ID NO:13 — 255 isomiR example 1 of SEQ ID NO: 15 — 256 isomiR example 2 of SEQID NO: 15 — 257 isomiR example 1 of SEQ ID NO: 18 — 258 isomiR example 2of SEQ ID NO: 18 — 259 isomiR example 1 of SEQ ID NO: 19 — 260 isomiRexample 2 of SEQ ID NO: 19 — 261 isomiR example 1 of SEQ ID NO: 20 — 262isomiR example 1 of SEQ ID NO: 23 — 263 isomiR example 2 of SEQ ID NO:23 — 264 isomiR example 1 of SEQ ID NO: 27 — 265 isomiR example 1 of SEQID NO: 30 — 266 isomiR example 2 of SEQ ID NO: 30 — 267 isomiR example 1of SEQ ID NO: 33 — 268 isomiR example 1 of SEQ ID NO: 34 — 269 isomiRexample 2 of SEQ ID NO: 34 — 270 isomiR example 1 of SEQ ID NO: 36 — 271isomiR example 1 of SEQ ID NO: 40 — 272 isomiR example 1 of SEQ ID NO:41 — 273 isomiR example 2 of SEQ ID NO: 41 — 274 isomiR example 1 of SEQID NO: 42 — 275 isomiR example 1 of SEQ ID NO: 43 — 276 isomiR example 2of SEQ ID NO: 43 — 277 isomiR example 1 of SEQ ID NO: 46 — 278 isomiRexample 1 of SEQ ID NO: 48 — 279 isomiR example 1 of SEQ ID NO: 51 — 280isomiR example 2 of SEQ ID NO: 51 — 281 isomiR example 1 of SEQ ID NO:54 — 282 isomiR example 1 of SEQ ID NO: 55 — 283 isomiR example 2 of SEQID NO: 55 — 284 isomiR example 1 of SEQ ID NO: 58 — 285 isomiR example 1of SEQ ID NO: 59 — 286 isomiR example 2 of SEQ ID NO: 59 — 287 isomiRexample 1 of SEQ ID NO: 60 — 288 isomiR example 2 of SEQ ID NO: 60 — 289isomiR example 1 of SEQ ID NO: 62 — 290 isomiR example 2 of SEQ ID NO:62 — 291 isomiR example 1 of SEQ ID NO: 63 — 292 isomiR example 1 of SEQID NO: 64 — 293 isomiR example 2 of SEQ ID NO: 64 — 294 isomiR example 1of SEQ ID NO: 66 — 295 isomiR example 2 of SEQ ID NO: 66 — 296 isomiRexample 1 of SEQ ID NO: 68 — 297 isomiR example 2 of SEQ ID NO: 68 — 298isomiR example 1 of SEQ ID NO: 71 — 299 isomiR example 1 of SEQ ID NO:72 — 300 isomiR example 1 of SEQ ID NO: 74 — 301 isomiR example 2 of SEQID NO: 74 — 302 isomiR example 1 of SEQ ID NO: 80 — 303 isomiR example 2of SEQ ID NO: 80 — 304 isomiR example 1 of SEQ ID NO: 82 — 305 isomiRexample 1 of SEQ ID NO: 83 — 306 isomiR example 1 of SEQ ID NO: 86 — 307isomiR example 1 of SEQ ID NO: 87 — 308 isomiR example 2 of SEQ ID NO:87 — 309 isomiR example 1 of SEQ ID NO: 89 — 310 isomiR example 1 of SEQID NO: 90 — 311 isomiR example 2 of SEQ ID NO: 90 — 312 isomiR example 1of SEQ ID NO: 92 — 313 isomiR example 2 of SEQ ID NO: 92 — 314 isomiRexample 1 of SEQ ID NO: 95 — 315 isomiR example 2 of SEQ ID NO: 95 — 316isomiR example 1 of SEQ ID NO: 99 — 317 isomiR example 2 of SEQ ID NO:99 — 318 isomiR example 1 of SEQ ID NO: 100 — 319 isomiR example 2 ofSEQ ID NO: 100 — 320 isomiR example 1 of SEQ ID NO: 101 — 321 isomiRexample 2 of SEQ ID NO: 101 — 322 isomiR example 1 of SEQ ID NO: 105 —323 isomiR example 2 of SEQ ID NO: 105 — 324 isomiR example 1 of SEQ IDNO: 106 — 325 isomiR example 2 of SEQ ID NO: 106 — 326 isomiR example 1of SEQ ID NO: 109 — 327 isomiR example 2 of SEQ ID NO: 109 — 328 isomiRexample 1 of SEQ ID NO: 110 — 329 isomiR example 2 of SEQ ID NO: 110 —330 isomiR example 1 of SEQ ID NO: 112 — 331 isomiR example 2 of SEQ IDNO: 112 — 332 isomiR example 1 of SEQ ID NO: 113 — 333 isomiR example 2of SEQ ID NO: 113 — 334 isomiR example 1 of SEQ ID NO: 115 — 335 isomiRexample 2 of SEQ ID NO: 115 — 336 isomiR example 1 of SEQ ID NO: 116 —337 isomiR example 2 of SEQ ID NO: 116 — 338 isomiR example 3 of SEQ IDNO: 116 — 339 isomiR example 1 of SEQ ID NO: 117 — 340 isomiR example 2of SEQ ID NO: 117 — 341 isomiR example 1 of SEQ ID NO: 118 — 342 isomiRexample 2 of SEQ ID NO: 118 — 343 isomiR example 3 of SEQ ID NO: 118 —344 isomiR example 1 of SEQ ID NO: 119 — 345 isomiR example 2 of SEQ IDNO: 119 — 346 isomiR example 1 of SEQ ID NO: 121 — 347 isomiR example 2of SEQ ID NO: 121 — 348 isomiR example 1 of SEQ ID NO: 122 — 349hsa-miR-4417 MIMAT0018929 350 hsa-miR-4707-5p MIMAT0019807 351hsa-miR-7847-3p MIMAT0030422 352 hsa-miR-2861 MIMAT0013802 353hsa-miR-4513 MIMAT0019050 354 hsa-miR-7111-5p MIMAT0028119 355hsa-miR-6777-5p MIMAT0027454 356 hsa-miR-7113-3p MIMAT0028124 357hsa-miR-4648 MIMAT0019710 358 hsa-miR-3184-5p MIMAT0015064 359hsa-miR-4271 MIMAT0016901 360 hsa-miR-6791-5p MIMAT0027482 361hsa-miR-642a-3p MIMAT0020924 362 hsa-miR-7108-5p MIMAT0028113 363hsa-miR-128-1-5p MIMAT0026477 364 hsa-miR-5196-5p MIMAT0021128 365hsa-miR-3178 MIMAT0015055 366 hsa-miR-3656 MIMAT0018076 367hsa-miR-92a-2-5p MIMAT0004508 368 hsa-miR-6769b-5p MIMAT0027620 369hsa-miR-4689 MIMAT0019778 370 hsa-miR-6076 MIMAT0023701 371hsa-miR-92b-5p MIMAT0004792 372 hsa-miR-6774-5p MIMAT0027448 373hsa-miR-486-3p MIMAT0004762 374 hsa-miR-6806-5p MIMAT0027512 375hsa-miR-6842-5p MIMAT0027586 376 hsa-miR-6716-5p MIMAT0025844 377hsa-miR-557 MIMAT0003221 378 hsa-miR-4673 MIMAT0019755 379 hsa-miR-4674MIMAT0019756 380 hsa-miR-4442 MIMAT0018960 381 hsa-miR-1915-3pMIMAT0007892 382 hsa-miR-4687-3p MIMAT0019775 383 hsa-miR-92b-3pMIMAT0003218 384 hsa-mir-4417 MI0016753 385 hsa-mir-4707 MI0017340 386hsa-mir-7847 MI0025517 387 hsa-mir-2861 MI0013006 388 hsa-mir-4513MI0016879 389 hsa-mir-7111 MI0022962 390 hsa-mir-6777 MI0022622 391hsa-mir-7113 MI0022964 392 hsa-mir-4648 MI0017275 393 hsa-mir-3184MI0014226 394 hsa-mir-4271 MI0015879 395 hsa-mir-6791 MI0022636 396hsa-mir-642a MI0003657 397 hsa-mir-7108 MI0022959 398 hsa-mir-128-1MI0000447 399 hsa-mir-5196 MI0018175 400 hsa-mir-3178 MI0014212 401hsa-mir-3656 MI0016056 402 hsa-mir-92a-2 MI0000094 403 hsa-mir-6769bMI0022706 404 hsa-mir-4689 MI0017322 405 hsa-mir-6076 MI0020353 406hsa-mir-92b MI0003560 407 hsa-mir-6774 MI0022619 408 hsa-mir-486MI0002470 409 hsa-mir-486-2 MI0023622 410 hsa-mir-6806 MI0022651 411hsa-mir-6842 MI0022688 412 hsa-mir-6716 MI0022550 413 hsa-mir-557MI0003563 414 hsa-mir-4673 MI0017304 415 hsa-mir-4674 MI0017305 416hsa-mir-4442 MI0016785 417 hsa-mir-1915 MI0008336 418 hsa-mir-4687MI0017319 419 hsa-mir-92b MI0003560 420 isomiR example 1 of SEQ ID NO:349 — 421 isomiR example 2 of SEQ ID NO: 349 — 422 isomiR example 1 ofSEQ ID NO: 350 — 423 isomiR example 2 of SEQ ID NO: 350 — 424 isomiRexample 1 of SEQ ID NO: 352 — 425 isomiR example 2 of SEQ ID NO: 352 —426 isomiR example 1 of SEQ ID NO: 353 — 427 isomiR example 2 of SEQ IDNO: 353 — 428 isomiR example 1 of SEQ ID NO: 357 — 429 isomiR example 2of SEQ ID NO: 357 — 430 isomiR example 1 of SEQ ID NO: 359 — 431 isomiRexample 2 of SEQ ID NO: 359 — 432 isomiR example 1 of SEQ ID NO: 361 —433 isomiR example 2 of SEQ ID NO: 361 — 434 isomiR example 1 of SEQ IDNO: 363 — 435 isomiR example 2 of SEQ ID NO: 363 — 436 isomiR example 1of SEQ ID NO: 364 — 437 isomiR example 2 of SEQ ID NO: 364 — 438 isomiRexample 1 of SEQ ID NO: 365 — 439 isomiR example 2 of SEQ ID NO: 365 —440 isomiR example 1 of SEQ ID NO: 366 — 441 isomiR example 2 of SEQ IDNO: 366 — 442 isomiR example 1 of SEQ ID NO: 367 — 443 isomiR example 2of SEQ ID NO: 367 — 444 isomiR example 1 of SEQ ID NO: 369 — 445 isomiRexample 2 of SEQ ID NO: 369 — 446 isomiR example 1 of SEQ ID NO: 371 —447 isomiR example 2 of SEQ ID NO: 371 — 448 isomiR example 1 of SEQ IDNO: 373 — 449 isomiR example 2 of SEQ ID NO: 373 — 450 isomiR example 1of SEQ ID NO: 376 — 451 isomiR example 2 of SEQ ID NO: 376 — 452 isomiRexample 1 of SEQ ID NO: 378 — 453 isomiR example 2 of SEQ ID NO: 378 —454 isomiR example 1 of SEQ ID NO: 379 — 455 isomiR example 2 of SEQ IDNO: 379 — 456 isomiR example 1 of SEQ ID NO: 380 — 457 isomiR example 2of SEQ ID NO: 380 — 458 isomiR example 1 of SEQ ID NO: 381 — 459 isomiRexample 2 of SEQ ID NO: 381 — 460 isomiR example 1 of SEQ ID NO: 382 —461 isomiR example 2 of SEQ ID NO: 382 — 462 isomiR example 1 of SEQ IDNO: 383 — 463 isomiR example 2 of SEQ ID NO: 383 — 464 hsa-miR-1203MIMAT0005866 465 hsa-miR-663b MIMAT0005867 466 hsa-miR-4258 MIMAT0016879467 hsa-miR-4649-5p MIMAT0019711 468 hsa-miR-4516 MIMAT0019053 469hsa-miR-3619-3p MIMAT0019219 470 hsa-miR-6826-5p MIMAT0027552 471hsa-miR-6757-5p MIMAT0027414 472 hsa-miR-3131 MIMAT0014996 473hsa-miR-1343-3p MIMAT0019776 474 hsa-mir-1203 MI0006335 475 hsa-mir-663bMI0006336 476 hsa-mir-4258 MI0015857 477 hsa-mir-4649 MI0017276 478hsa-mir-4516 MI0016882 479 hsa-mir-3619 MI0016009 480 hsa-mir-6826MI0022671 481 hsa-mir-6757 MI0022602 482 hsa-mir-3131 MI0014151 483hsa-mir-1343 MI0017320 484 isomiR example 1 of SEQ ID NO: 465 — 485isomiR example 2 of SEQ ID NO: 465 — 486 isomiR example 1 of SEQ ID NO:468 — 487 isomiR example 2 of SEQ ID NO: 468 — 488 isomiR example 1 ofSEQ ID NO: 472 — 489 isomiR example 2 of SEQ ID NO: 472 — 490 isomiRexample 1 of SEQ ID NO: 473 — 491 isomiR example 2 of SEQ ID NO: 473 —492 hsa-miR-6775-5p MIMAT0027450 493 hsa-miR-6813-5p MIMAT0027526 494hsa-miR-3940-5p MIMAT0019229 495 hsa-mir-6775 MI0022620 496 hsa-mir-6813MI0022658 497 hsa-mir-3940 MI0016597 498 isomiR example 1 of SEQ ID NO:494 — 499 isomiR example 2 of SEQ ID NO: 494 —

The present specification encompasses the contents described in thespecifications and/or drawings of Japanese Patent Application No.2014-113523 and No. 2014-185730 from which the present applicationclaims priorities.

Advantageous Effect of Invention

According to the present invention, pancreatic cancer can be detectedeasily and in high accuracy.

For example, the presence or absence of pancreatic cancer in patientscan be easily detected by using, as indicators, the determinedexpression levels of several miRNAs in blood, serum, and/or plasma ofthe patients, which can be collected with limited invasiveness.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 This figure shows the relationship between the nucleotidesequences of hsa-miR-4665-5p represented by SEQ ID NO: 36 andhsa-miR-4665-3p represented by SEQ ID NO: 103, which are produced from aprecursor hsa-mir-4665 represented by SEQ ID NO: 159.

FIG. 2 Left diagram: the expression level measurement values ofhsa-miR-6893-5p (SEQ ID NO: 1) in healthy subjects (100 persons) andpancreatic cancer patients (67 persons) selected as a training cohortwere each plotted on the ordinate. The horizontal line in the diagramdepicts a threshold (8.02) that was optimized by Fisher's discriminantanalysis and discriminated between the two groups. Right diagram: theexpression level measurement values of hsa-miR-6893-5p (SEQ ID NO: 1) inhealthy subjects (50 persons) and pancreatic cancer patients (33persons) selected as a validation cohort were each plotted on theordinate. The horizontal line in the diagram depicts the threshold(8.02) that was set in the training cohort and discriminated between thetwo groups.

FIG. 3 Left diagram: the expression level measurement values ofhsa-miR-6893-5p (SEQ ID NO: 1) in healthy subjects (100 persons,circles) and pancreatic cancer patients (67 persons, triangles) selectedas a training cohort were each plotted on the abscissa against theirexpression level measurement values of hsa-miR-6075 (SEQ ID NO: 2) onthe ordinate. The line in the diagram depicts a discriminant function(0=1.74x+y+5.14) that was optimized by Fisher's discriminant analysisand discriminated between the two groups. Right diagram: the expressionlevel measurement values of hsa-miR-6893-5p (SEQ ID NO: 1) in healthysubjects (50 persons, circles) and pancreatic cancer patients (33persons, triangles) selected as a validation cohort were each plotted onthe abscissa against their expression level measurement values ofhsa-miR-6075 (SEQ ID NO: 2) on the ordinate. The line in the diagramdepicts the threshold (0=1.74x+y+5.14) that was set in the trainingcohort and discriminated between the two groups.

FIG. 4 Upper diagram: a discriminant(1.64×hsa-miR-6075+1.02×hsa-miR-6836-3p−0.35×hsa-miR-6799-5p−0.06×hsa-miR-125a-3p−20.67)was prepared by use of Fisher's discriminant analysis from theexpression level measurement values of hsa-miR-6075 (SEQ ID NO: 2),hsa-miR-6836-3p (SEQ ID NO: 7), hsa-miR-6799-5p (SEQ ID NO: 9), andhsa-miR-125a-3p (SEQ ID NO: 105) in 67 pancreatic cancer patients, 93healthy subjects, 35 colorectal cancer patients, 37 stomach cancerpatients, 32 esophageal cancer patients, 38 liver cancer patients, and13 benign pancreaticobiliary disease patients selected as a trainingcohort, and discriminant scores obtained from the discriminant wereplotted on the ordinate against the sample groups on the abscissa. Thedotted line in the diagram depicts a discriminant boundary that offereda discriminant score of 0 and discriminated between the groups. Lowerdiagram: discriminant scores obtained from the discriminant preparedfrom the training cohort as to the expression level measurement valuesof hsa-miR-6075 (SEQ ID NO: 2), hsa-miR-6799-5p (SEQ ID NO: 9),hsa-miR-125a-3p (SEQ ID NO: 105), and hsa-miR-6836-3p (SEQ ID NO: 7) in33 pancreatic cancer patients, 57 healthy subjects, 15 colorectal cancerpatients, 13 stomach cancer patients, 18 esophageal cancer patients, 12liver cancer patients, and 8 benign pancreaticobiliary disease patientsselected as a validation cohort were plotted on the ordinate against thesample groups on the abscissa. The dotted line in the diagram depictsthe discriminant boundary that offered a discriminant score of 0 anddiscriminated between both of the groups.

MODES FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be further described in detail.

1. Target Nucleic Acid for Pancreatic Cancer

Primary target nucleic acids, as pancreatic cancer markers, fordetecting the presence and/or absence of pancreatic cancer or pancreaticcancer cells using the nucleic acid probes or the primers for thedetection of pancreatic cancer defined above according to the presentinvention comprise at least one or more miRNAs selected from the groupconsisting of the following miRNAs: hsa-miR-6893-5p, hsa-miR-6075,hsa-miR-6820-5p, hsa-miR-4294, hsa-miR-6729-5p, hsa-miR-4476,hsa-miR-6836-3p, hsa-miR-6765-3p, hsa-miR-6799-5p, hsa-miR-4530,hsa-miR-7641, hsa-miR-4454, hsa-miR-615-5p, hsa-miR-8073, hsa-miR-663a,hsa-miR-4634, hsa-miR-4450, hsa-miR-4792, hsa-miR-665, hsa-miR-7975,hsa-miR-7109-5p, hsa-miR-6789-5p, hsa-miR-4497, hsa-miR-6877-5p,hsa-miR-6880-5p, hsa-miR-7977, hsa-miR-4734, hsa-miR-6821-5p,hsa-miR-8089, hsa-miR-5585-3p, hsa-miR-6085, hsa-miR-6845-5p,hsa-miR-4651, hsa-miR-4433-3p, hsa-miR-1231, hsa-miR-4665-5p,hsa-miR-7114-5p, hsa-miR-1238-5p, hsa-miR-8069, hsa-miR-4732-5p,hsa-miR-619-5p, hsa-miR-3622a-5p, hsa-miR-1260a, hsa-miR-6741-5p,hsa-miR-6781-5p, hsa-miR-6125, hsa-miR-6805-5p, hsa-miR-6132,hsa-miR-6872-3p, hsa-miR-6875-5p, hsa-miR-1908-3p, hsa-miR-4433b-3p,hsa-miR-4736, hsa-miR-5100, hsa-miR-6724-5p, hsa-miR-7107-5p,hsa-miR-6726-5p, hsa-miR-3185, hsa-miR-4638-5p, hsa-miR-1273g-3p,hsa-miR-6778-5p, hsa-miR-328-5p, hsa-miR-3679-3p, hsa-miR-1228-3p,hsa-miR-6779-5p, hsa-miR-4723-5p, hsa-miR-6850-5p, hsa-miR-760,hsa-miR-7704, hsa-miR-8072, hsa-miR-4486, hsa-miR-1913, hsa-miR-4656,hsa-miR-1260b, hsa-miR-7106-5p, hsa-miR-6889-5p, hsa-miR-6780b-5p,hsa-miR-6090, hsa-miR-4534, hsa-miR-4449, hsa-miR-5195-3p, hsa-miR-1202,hsa-miR-4467, hsa-miR-6515-3p, hsa-miR-4281, hsa-miR-4505, hsa-miR-4484,hsa-miR-6805-3p, hsa-miR-3135b, hsa-miR-3162-5p, hsa-miR-6768-5p,hsa-miR-6721-5p, hsa-miR-1227-5p, hsa-miR-6722-3p, hsa-miR-4286,hsa-miR-4746-3p, hsa-miR-6727-5p, hsa-miR-6816-5p, hsa-miR-4741,hsa-miR-4508, hsa-miR-940, hsa-miR-4327, hsa-miR-4665-3p, hsa-miR-718,hsa-miR-1203, hsa-miR-663b, hsa-miR-4258, hsa-miR-4649-5p, hsa-miR-4516,hsa-miR-3619-3p, hsa-miR-6826-5p, hsa-miR-6757-5p, hsa-miR-3131,hsa-miR-1343-3p, hsa-miR-6775-5p, hsa-miR-6813-5p and hsa-miR-3940-5p.Furthermore, at least one or more miRNAs selected from the groupconsisting of the following other pancreatic cancer markers that can becombined with these miRNAs, i.e., hsa-miR-125a-3p, hsa-miR-204-3p,hsa-miR-1469, hsa-miR-575, hsa-miR-150-3p, hsa-miR-423-5p, hsa-miR-564,hsa-miR-3188, hsa-miR-1246, hsa-miR-602, hsa-miR-1290, hsa-miR-16-5p,hsa-miR-451a, hsa-miR-24-3p, hsa-miR-187-5p, hsa-miR-1908-5p,hsa-miR-371a-5p and hsa-miR-550a-5p can also be preferably used astarget nucleic acids. Moreover, at least one or more miRNAs selectedfrom the group consisting of the following other pancreatic cancermarkers that can be combined with these miRNAs, i.e., hsa-miR-4417,hsa-miR-4707-5p, hsa-miR-7847-3p, hsa-miR-2861, hsa-miR-4513,hsa-miR-7111-5p, hsa-miR-6777-5p, hsa-miR-7113-3p, hsa-miR-4648,hsa-miR-3184-5p, hsa-miR-4271, hsa-miR-6791-5p, hsa-miR-642a-3p,hsa-miR-7108-5p, hsa-miR-128-1-5p, hsa-miR-5196-5p, hsa-miR-3178,hsa-miR-3656, hsa-miR-92a-2-5p, hsa-miR-6769b-5p, hsa-miR-4689,hsa-miR-6076, hsa-miR-92b-5p, hsa-miR-6774-5p, hsa-miR-486-3p,hsa-miR-6806-5p, hsa-miR-6842-5p, hsa-miR-6716-5p, hsa-miR-557,hsa-miR-4673, hsa-miR-4674, hsa-miR-4442, hsa-miR-1915-3p,hsa-miR-4687-3p and hsa-miR-92b-3p can also be preferably used as targetnucleic acids.

These miRNAs include, for example, a human gene comprising a nucleotidesequence represented by any of SEQ ID NOs: 1 to 122 and 349 to 383, 464to 473, and 492 to 494 (i.e., hsa-miR-6893-5p, hsa-miR-6075,hsa-miR-6820-5p, hsa-miR-4294, hsa-miR-6729-5p, hsa-miR-4476,hsa-miR-6836-3p, hsa-miR-6765-3p, hsa-miR-6799-5p, hsa-miR-4530,hsa-miR-7641, hsa-miR-4454, hsa-miR-615-5p, hsa-miR-8073, hsa-miR-663a,hsa-miR-4634, hsa-miR-4450, hsa-miR-4792, hsa-miR-665, hsa-miR-7975,hsa-miR-7109-5p, hsa-miR-6789-5p, hsa-miR-4497, hsa-miR-6877-5p,hsa-miR-6880-5p, hsa-miR-7977, hsa-miR-4734, hsa-miR-6821-5p,hsa-miR-8089, hsa-miR-5585-3p, hsa-miR-6085, hsa-miR-6845-5p,hsa-miR-4651, hsa-miR-4433-3p, hsa-miR-1231, hsa-miR-4665-5p,hsa-miR-7114-5p, hsa-miR-1238-5p, hsa-miR-8069, hsa-miR-4732-5p,hsa-miR-619-5p, hsa-miR-3622a-5p, hsa-miR-1260a, hsa-miR-6741-5p,hsa-miR-6781-5p, hsa-miR-6125, hsa-miR-6805-5p, hsa-miR-6132,hsa-miR-6872-3p, hsa-miR-6875-5p, hsa-miR-1908-3p, hsa-miR-4433b-3p,hsa-miR-4736, hsa-miR-5100, hsa-miR-6724-5p, hsa-miR-7107-5p,hsa-miR-6726-5p, hsa-miR-3185, hsa-miR-4638-5p, hsa-miR-1273g-3p,hsa-miR-6778-5p, hsa-miR-328-5p, hsa-miR-3679-3p, hsa-miR-1228-3p,hsa-miR-6779-5p, hsa-miR-4723-5p, hsa-miR-6850-5p, hsa-miR-760,hsa-miR-7704, hsa-miR-8072, hsa-miR-4486, hsa-miR-1913, hsa-miR-4656,hsa-miR-1260b, hsa-miR-7106-5p, hsa-miR-6889-5p, hsa-miR-6780b-5p,hsa-miR-6090, hsa-miR-4534, hsa-miR-4449, hsa-miR-5195-3p, hsa-miR-1202,hsa-miR-4467, hsa-miR-6515-3p, hsa-miR-4281, hsa-miR-4505, hsa-miR-4484,hsa-miR-6805-3p, hsa-miR-3135b, hsa-miR-3162-5p, hsa-miR-6768-5p,hsa-miR-6721-5p, hsa-miR-1227-5p, hsa-miR-6722-3p, hsa-miR-4286,hsa-miR-4746-3p, hsa-miR-6727-5p, hsa-miR-6816-5p, hsa-miR-4741,hsa-miR-4508, hsa-miR-940, hsa-miR-4327, hsa-miR-4665-3p, hsa-miR-718,hsa-miR-125a-3p, hsa-miR-204-3p, hsa-miR-1469, hsa-miR-575,hsa-miR-150-3p, hsa-miR-423-5p, hsa-miR-564, hsa-miR-3188, hsa-miR-1246,hsa-miR-602, hsa-miR-1290, hsa-miR-16-5p, hsa-miR-451a, hsa-miR-24-3p,hsa-miR-187-5p, hsa-miR-1908-5p, hsa-miR-371a-5p, hsa-miR-550a-5p,hsa-miR-4417, hsa-miR-4707-5p, hsa-miR-7847-3p, hsa-miR-2861,hsa-miR-4513, hsa-miR-7111-5p, hsa-miR-6777-5p, hsa-miR-7113-3p,hsa-miR-4648, hsa-miR-3184-5p, hsa-miR-4271, hsa-miR-6791-5p,hsa-miR-642a-3p, hsa-miR-7108-5p, hsa-miR-128-1-5p, hsa-miR-5196-5p,hsa-miR-3178, hsa-miR-3656, hsa-miR-92a-2-5p, hsa-miR-6769b-5p,hsa-miR-4689, hsa-miR-6076, hsa-miR-92b-5p, hsa-miR-6774-5p,hsa-miR-486-3p, hsa-miR-6806-5p, hsa-miR-6842-5p, hsa-miR-6716-5p,hsa-miR-557, hsa-miR-4673, hsa-miR-4674, hsa-miR-4442, hsa-miR-1915-3p,hsa-miR-4687-3p, hsa-miR-92b-3p, hsa-miR-1203, hsa-miR-663b,hsa-miR-4258, hsa-miR-4649-5p, hsa-miR-4516, hsa-miR-3619-3p,hsa-miR-6826-5p, hsa-miR-6757-5p, hsa-miR-3131, hsa-miR-1343-3p,hsa-miR-6775-5p, hsa-miR-6813-5p and hsa-miR-3940-5p, respectively), acongener, a transcript thereof, or/and a variant or a derivativethereof. In this context, the gene, the congener, the transcript, thevariant, and the derivative are as defined above.

The target nucleic acid is preferably a human gene comprising anucleotide sequence represented by any of SEQ ID NOs: 1 to 499 or atranscript thereof, more preferably the transcript, i.e., a miRNA or itsprecursor RNA (pri-miRNA or pre-miRNA).

The first target gene is the hsa-miR-6893-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The second target gene is the hsa-miR-6075 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The third target gene is the hsa-miR-6820-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The fourth target gene is the hsa-miR-4294 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The fifth target gene is the hsa-miR-6729-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The sixth target gene is the hsa-miR-4476 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The seventh target gene is the hsa-miR-6836-3p gene, a congener thereof,a transcript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The eighth target gene is the hsa-miR-6765-3p gene, a congener thereof,a transcript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The ninth target gene is the hsa-miR-6799-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 10th target gene is the hsa-miR-4530 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 11th target gene is the hsa-miR-7641 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 12th target gene is the hsa-miR-4454 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 13th target gene is the hsa-miR-615-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 14th target gene is the hsa-miR-8073 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 15th target gene is the hsa-miR-663a gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 16th target gene is the hsa-miR-4634 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 17th target gene is the hsa-miR-4450 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 18th target gene is the hsa-miR-4792 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 19th target gene is the hsa-miR-665 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 20th target gene is the hsa-miR-7975 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 21st target gene is the hsa-miR-7109-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 22nd target gene is the hsa-miR-6789-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 23rd target gene is the hsa-miR-4497 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 24th target gene is the hsa-miR-6877-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 25th target gene is the hsa-miR-6880-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 26th target gene is the hsa-miR-7977 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 27th target gene is the hsa-miR-4734 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 28th target gene is the hsa-miR-6821-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 29th target gene is the hsa-miR-8089 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 30th target gene is the hsa-miR-5585-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 31st target gene is the hsa-miR-6085 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 32nd target gene is the hsa-miR-6845-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 33rd target gene is the hsa-miR-4651 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 34th target gene is the hsa-miR-4433-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 35th target gene is the hsa-miR-1231 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 36th target gene is the hsa-miR-4665-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 37th target gene is the hsa-miR-7114-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 38th target gene is the hsa-miR-1238-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 39th target gene is the hsa-miR-8069 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 40th target gene is the hsa-miR-4732-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 41st target gene is the hsa-miR-619-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 42nd target gene is the hsa-miR-3622a-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 43rd target gene is the hsa-miR-1260a gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 44th target gene is the hsa-miR-6741-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 45th target gene is the hsa-miR-6781-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 46th target gene is the hsa-miR-6125 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 47th target gene is the hsa-miR-6805-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 48th target gene is the hsa-miR-6132 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 49th target gene is the hsa-miR-6872-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 50th target gene is the hsa-miR-6875-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 51st target gene is the hsa-miR-1908-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 52nd target gene is the hsa-miR-4433b-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 53rd target gene is the hsa-miR-4736 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 54th target gene is the hsa-miR-5100 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 55th target gene is the hsa-miR-6724-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 56th target gene is the hsa-miR-7107-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 57th target gene is the hsa-miR-6726-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 58th target gene is the hsa-miR-3185 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 59th target gene is the hsa-miR-4638-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 60th target gene is the hsa-miR-1273g-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 61st target gene is the hsa-miR-6778-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 62nd target gene is the hsa-miR-328-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 63rd target gene is the hsa-miR-3679-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 64th target gene is the hsa-miR-1228-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 65th target gene is the hsa-miR-6779-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 66th target gene is the hsa-miR-4723-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 67th target gene is the hsa-miR-6850-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 68th target gene is the hsa-miR-760 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 69th target gene is the hsa-miR-7704 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 70th target gene is the hsa-miR-8072 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 71st target gene is the hsa-miR-4486 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 72nd target gene is the hsa-miR-1913 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 73rd target gene is the hsa-miR-4656 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 74th target gene is the hsa-miR-1260b gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 75th target gene is the hsa-miR-7106-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 76th target gene is the hsa-miR-6889-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 77th target gene is the hsa-miR-6780b-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 78th target gene is the hsa-miR-6090 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 79th target gene is the hsa-miR-4534 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 80th target gene is the hsa-miR-4449 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 81st target gene is the hsa-miR-5195-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 82nd target gene is the hsa-miR-1202 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 83rd target gene is the hsa-miR-4467 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 84th target gene is the hsa-miR-6515-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 85th target gene is the hsa-miR-4281 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 86th target gene is the hsa-miR-4505 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 87th target gene is the hsa-miR-4484 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 88th target gene is the hsa-miR-6805-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 89th target gene is the hsa-miR-3135b gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 90th target gene is the hsa-miR-3162-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 91st target gene is the hsa-miR-6768-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 92nd target gene is the hsa-miR-6721-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 93rd target gene is the hsa-miR-1227-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 94th target gene is the hsa-miR-6722-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 95th target gene is the hsa-miR-4286 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 96th target gene is the hsa-miR-4746-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 97th target gene is the hsa-miR-6727-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 98th target gene is the hsa-miR-6816-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 99th target gene is the hsa-miR-4741 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 100th target gene is the hsa-miR-4508 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 101st target gene is the hsa-miR-940 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 102nd target gene is the hsa-miR-4327 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 103rd target gene is the hsa-miR-4665-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 104th target gene is the hsa-miR-718 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 105th target gene is the hsa-miR-125a-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer (PatentLiterature 1 described above).

The 106th target gene is the hsa-miR-204-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer (PatentLiterature 2 described above).

The 107th target gene is the hsa-miR-1469 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer(Non-Patent Literature 4 described above).

The 108th target gene is the hsa-miR-575 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer (PatentLiterature 3 described above).

The 109th target gene is the hsa-miR-150-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer(Non-Patent Literature 4 described above).

The 110th target gene is the hsa-miR-423-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer (PatentLiterature 2 described above).

The 111th target gene is the hsa-miR-564 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer(Non-Patent Literature 4 described above).

The 112th target gene is the hsa-miR-3188 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer(Non-Patent Literature 5 described above).

The 113th target gene is the hsa-miR-1246 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer(Non-Patent Literature 4 described above).

The 114th target gene is the hsa-miR-602 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer(Non-Patent Literature 7 described above).

The 115th target gene is the hsa-miR-1290 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer(Non-Patent Literature 6 described above).

The 116th target gene is the hsa-miR-16-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer (PatentLiterature 3 described above).

The 117th target gene is the hsa-miR-451a gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer (PatentLiterature 4 described above).

The 118th target gene is the hsa-miR-24-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer (PatentLiterature 3 described above).

The 119th target gene is the hsa-miR-187-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer (PatentLiterature 5 described above).

The 120th target gene is the hsa-miR-1908-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer(Non-Patent Literature 4 described above).

The 121st target gene is the hsa-miR-371a-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer(Non-Patent Literature 4 described above).

The 122nd target gene is the hsa-miR-550a-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. The previouslyknown report shows that change in the expression of the gene or thetranscript thereof can serve as a marker for pancreatic cancer(Non-Patent Literature 6 described above).

The 123rd target gene is the hsa-miR-4417 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 124th target gene is the hsa-miR-4707-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 125th target gene is the hsa-miR-7847-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 126th target gene is the hsa-miR-2861 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 127th target gene is the hsa-miR-4513 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 128th target gene is the hsa-miR-7111-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 129th target gene is the hsa-miR-6777-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 130th target gene is the hsa-miR-7113-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 131st target gene is the hsa-miR-4648 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 132nd target gene is the hsa-miR-3184-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 133rd target gene is the hsa-miR-4271 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 134th target gene is the hsa-miR-6791-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 135th target gene is the hsa-miR-642a-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 136th target gene is the hsa-miR-7108-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 137th target gene is the hsa-miR-128-1-5p gene, a congener thereof,a transcript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 138th target gene is the hsa-miR-5196-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 139th target gene is the hsa-miR-3178 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 140th target gene is the hsa-miR-3656 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 141st target gene is the hsa-miR-92a-2-5p gene, a congener thereof,a transcript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 142nd target gene is the hsa-miR-6769b-5p gene, a congener thereof,a transcript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 143rd target gene is the hsa-miR-4689 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 144th target gene is the hsa-miR-6076 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 145th target gene is the hsa-miR-92b-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 146th target gene is the hsa-miR-6774-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 147th target gene is the hsa-miR-486-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 148th target gene is the hsa-miR-6806-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 149th target gene is the hsa-miR-6842-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 150th target gene is the hsa-miR-6716-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 151st target gene is the hsa-miR-557 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 152nd target gene is the hsa-miR-4673 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 153rd target gene is the hsa-miR-4674 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 154th target gene is the hsa-miR-4442 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 155th target gene is the hsa-miR-1915-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 156th target gene is the hsa-miR-4687-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 157th target gene is the hsa-miR-92b-3p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 158th target gene is the hsa-miR-1203 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 159th target gene is the hsa-mir-663b gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 160th target gene is the hsa-mir-4258 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 161st target gene is the hsa-mir-4649 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 162nd target gene is the hsa-mir-4516 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 163rd target gene is the hsa-mir-3619 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 164th target gene is the hsa-mir-6826 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 165th target gene is the hsa-mir-6757 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 166th target gene is the hsa-mir-3131 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 167th target gene is the hsa-mir-1343 gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 168th target gene is the hsa-miR-6775-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 169th target gene is the hsa-miR-6813-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

The 170th target gene is the hsa-miR-3940-5p gene, a congener thereof, atranscript thereof, or a variant or a derivative thereof. None of thepreviously known reports show that change in the expression of the geneor the transcript thereof can serve as a marker for pancreatic cancer.

2. Nucleic Acid Probe or Primer for Detection of Pancreatic Cancer

In the present invention, a nucleic acid capable of specifically bindingto any of the target nucleic acids as the pancreatic cancer markersdescribed above can be used as a nucleic acid, for example, a nucleicacid probe or a primer, for the detection or diagnosis of pancreaticcancer.

In the present invention, the nucleic acid probes or the primers thatcan be used for detecting pancreatic cancer or for diagnosing pancreaticcancer enable qualitative and/or quantitative measurement of thepresence, expression level, or existing amount (abundance) of: any ofhuman-derived hsa-miR-6893-5p, hsa-miR-6075, hsa-miR-6820-5p,hsa-miR-4294, hsa-miR-6729-5p, hsa-miR-4476, hsa-miR-6836-3p,hsa-miR-6765-3p, hsa-miR-6799-5p, hsa-miR-4530, hsa-miR-7641,hsa-miR-4454, hsa-miR-615-5p, hsa-miR-8073, hsa-miR-663a, hsa-miR-4634,hsa-miR-4450, hsa-miR-4792, hsa-miR-665, hsa-miR-7975, hsa-miR-7109-5p,hsa-miR-6789-5p, hsa-miR-4497, hsa-miR-6877-5p, hsa-miR-6880-5p,hsa-miR-7977, hsa-miR-4734, hsa-miR-6821-5p, hsa-miR-8089,hsa-miR-5585-3p, hsa-miR-6085, hsa-miR-6845-5p, hsa-miR-4651,hsa-miR-4433-3p, hsa-miR-1231, hsa-miR-4665-5p, hsa-miR-7114-5p,hsa-miR-1238-5p, hsa-miR-8069, hsa-miR-4732-5p, hsa-miR-619-5p,hsa-miR-3622a-5p, hsa-miR-1260a, hsa-miR-6741-5p, hsa-miR-6781-5p,hsa-miR-6125, hsa-miR-6805-5p, hsa-miR-6132, hsa-miR-6872-3p,hsa-miR-6875-5p, hsa-miR-1908-3p, hsa-miR-4433b-3p, hsa-miR-4736,hsa-miR-5100, hsa-miR-6724-5p, hsa-miR-7107-5p, hsa-miR-6726-5p,hsa-miR-3185, hsa-miR-4638-5p, hsa-miR-1273g-3p, hsa-miR-6778-5p,hsa-miR-328-5p, hsa-miR-3679-3p, hsa-miR-1228-3p, hsa-miR-6779-5p,hsa-miR-4723-5p, hsa-miR-6850-5p, hsa-miR-760, hsa-miR-7704,hsa-miR-8072, hsa-miR-4486, hsa-miR-1913, hsa-miR-4656, hsa-miR-1260b,hsa-miR-7106-5p, hsa-miR-6889-5p, hsa-miR-6780b-5p, hsa-miR-6090,hsa-miR-4534, hsa-miR-4449, hsa-miR-5195-3p, hsa-miR-1202, hsa-miR-4467,hsa-miR-6515-3p, hsa-miR-4281, hsa-miR-4505, hsa-miR-4484,hsa-miR-6805-3p, hsa-miR-3135b, hsa-miR-3162-5p, hsa-miR-6768-5p,hsa-miR-6721-5p, hsa-miR-1227-5p, hsa-miR-6722-3p, hsa-miR-4286,hsa-miR-4746-3p, hsa-miR-6727-5p, hsa-miR-6816-5p, hsa-miR-4741,hsa-miR-4508, hsa-miR-940, hsa-miR-4327, hsa-miR-4665-3p, hsa-miR-718,hsa-miR-1203, hsa-miR-663b, hsa-miR-4258, hsa-miR-4649-5p, hsa-miR-4516,hsa-miR-3619-3p, hsa-miR-6826-5p, hsa-miR-6757-5p, hsa-miR-3131,hsa-miR-1343-3p, hsa-miR-6775-5p, hsa-miR-6813-5p, and hsa-miR-3940-5p,as target nucleic acids for pancreatic cancer, or a combination thereof;and hsa-miR-125a-3p, hsa-miR-204-3p, hsa-miR-1469, hsa-miR-575,hsa-miR-150-3p, hsa-miR-423-5p, hsa-miR-564, hsa-miR-3188, hsa-miR-1246,hsa-miR-602, hsa-miR-1290, hsa-miR-16-5p, hsa-miR-451a, hsa-miR-24-3p,hsa-miR-187-5p, hsa-miR-1908-5p, hsa-miR-371a-5p, and hsa-miR-550a-5p,that can be further optionally combined therewith or a combinationthereof, and hsa-miR-4417, hsa-miR-4707-5p, hsa-miR-7847-3p,hsa-miR-2861, hsa-miR-4513, hsa-miR-7111-5p, hsa-miR-6777-5p,hsa-miR-7113-3p, hsa-miR-4648, hsa-miR-3184-5p, hsa-miR-4271,hsa-miR-6791-5p, hsa-miR-642a-3p, hsa-miR-7108-5p, hsa-miR-128-1-5p,hsa-miR-5196-5p, hsa-miR-3178, hsa-miR-3656, hsa-miR-92a-2-5p,hsa-miR-6769b-5p, hsa-miR-4689, hsa-miR-6076, hsa-miR-92b-5p,hsa-miR-6774-5p, hsa-miR-486-3p, hsa-miR-6806-5p, hsa-miR-6842-5p,hsa-miR-6716-5p, hsa-miR-557, hsa-miR-4673, hsa-miR-4674, hsa-miR-4442,hsa-miR-1915-3p, hsa-miR-4687-3p and hsa-miR-92b-3p, that can be furtheroptionally combined therewith or a combination thereof; congenersthereof: transcripts thereof: or variants or derivatives thereof.

The expression levels of the target nucleic acids described above areincreased or decreased (hereinafter, referred to as“increased/decreased”) depending on the types of the target nucleicacids in subjects having pancreatic cancer as compared with healthysubjects. Hence, the composition of the present invention can beeffectively used for measuring expression levels of the target nucleicacids in body fluids from subjects (e.g., humans) suspected of havingpancreatic cancer and body fluids from healthy subjects and therebydetecting pancreatic cancer through the comparison thereof. Thecomposition of the invention can also be effectively used for measuringexpression levels of the target nucleic acids in body fluids fromsubjects (e.g., humans) suspected of having pancreatic cancer and bodyfluids from colorectal cancer patients, stomach cancer patients,esophageal cancer patients, liver cancer patients, and benignpancreaticobiliary disease patients and thereby specifically detectingpancreatic cancer while distinguished from other cancers, benigndiseases or the like, through the comparison thereof.

The nucleic acid probe or the primer that can be used in the presentinvention is a nucleic acid probe capable of specifically binding to apolynucleotide consisting of a nucleotide sequence represented by atleast one of SEQ ID NOs: 1 to 104, 464 to 473, and 492 to 494, or aprimer for amplifying a polynucleotide consisting of a nucleotidesequence represented by at least one of SEQ ID NOs: 1 to 104, 464 to473, and 492 to 494.

The nucleic acid probe or the primer that can be used in the presentinvention may further comprise a nucleic acid probe capable ofspecifically binding to a polynucleotide consisting of a nucleotidesequence represented by at least one of SEQ ID NOs: 105 to 122, or aprimer for amplifying a polynucleotide consisting of a nucleotidesequence represented by at least one of SEQ ID NOs: 105 to 122.

The nucleic acid probe or the primer that can be used in the presentinvention may further comprise a nucleic acid probe capable ofspecifically binding to a polynucleotide consisting of a nucleotidesequence represented by at least one of SEQ ID NOs: 349 to 383, or aprimer for amplifying a polynucleotide consisting of a nucleotidesequence represented by at least one of SEQ ID NOs: 349 to 383.

Specifically, these nucleic acid probes or primers comprise acombination of one or more polynucleotides selected from: a group ofpolynucleotides comprising nucleotide sequences represented by any ofSEQ ID NOs: 1 to 122, 349 to 383, 464 to 473, and 492 to 494 ornucleotide sequences derived from the nucleotide sequences by thereplacement of u with t, and a group of complementary polynucleotidesthereof; a group of polynucleotides respectively hybridizing understringent conditions (mentioned later) to DNAs consisting of nucleotidesequences complementary to these nucleotide sequences, and a group ofcomplementary polynucleotides thereof; and a group of polynucleotidescomprising 15 or more, preferably 17 or more consecutive nucleotides andbeing from the nucleotide sequences of these polynucleotide groups.These polynucleotides can be used as nucleic acid probes and primers fordetecting the pancreatic cancer markers as target nucleic acids.

More specifically, examples of the nucleic acid probes or the primersthat can be used in the present invention include one or morepolynucleotides selected from the group consisting of the followingpolynucleotides (a) to (e):

(a) a polynucleotide consisting of a nucleotide sequence represented byany of SEQ ID NOs: 1 to 104, 464 to 473, and 492 to 494 or a nucleotidesequence derived from the nucleotide sequence by the replacement of uwith t, a variant thereof, a derivative thereof, or a fragment thereofcomprising 15 or more consecutive nucleotides;(b) a polynucleotide comprising a nucleotide sequence represented by anyof SEQ ID NOs: 1 to 104, 464 to 473, and 492 to 494;(c) a polynucleotide consisting of a nucleotide sequence complementaryto a nucleotide sequence represented by any of SEQ ID NOs: 1 to 104, 464to 473, and 492 to 494 or a nucleotide sequence derived from thenucleotide sequence by the replacement of u with t, a variant thereof, aderivative thereof, or a fragment thereof comprising 15 or moreconsecutive nucleotides;(d) a polynucleotide comprising a nucleotide sequence complementary to anucleotide sequence represented by any of SEQ ID NOs: 1 to 104, 464 to473, and 492 to 494 or a nucleotide sequence derived from the nucleotidesequence by the replacement of u with t; and(e) a polynucleotide hybridizing under stringent conditions to any ofthe polynucleotides (a) to (d).

In addition to at least one or more polynucleotides selected from any ofthe polynucleotides (a) to (e), the nucleic acid probes or the primersthat can be used in the present invention may further comprise any ofthe following polynucleotides (f) to (j):

(f) a polynucleotide consisting of a nucleotide sequence represented byany of SEQ ID NOs: 105 to 122 or a nucleotide sequence derived from thenucleotide sequence by the replacement of u with t, a variant thereof, aderivative thereof, or a fragment thereof comprising 15 or moreconsecutive nucleotides;(g) a polynucleotide comprising a nucleotide sequence represented by anyof SEQ ID NOs: 105 to 122;(h) a polynucleotide consisting of a nucleotide sequence complementaryto a nucleotide sequence represented by any of SEQ ID NOs: 105 to 122 ora nucleotide sequence derived from the nucleotide sequence by thereplacement of u with t, a variant thereof, a derivative thereof, or afragment thereof comprising 15 or more consecutive nucleotides;(i) a polynucleotide comprising a nucleotide sequence complementary to anucleotide sequence represented by any of SEQ ID NOs: 105 to 122 or anucleotide sequence derived from the nucleotide sequence by thereplacement of u with t; and(j) a polynucleotide hybridizing under stringent conditions to any ofthe polynucleotides (0 to (i).

In addition to at least one or more polynucleotides selected from any ofthe polynucleotides (a) to (j), the nucleic acid probes or the primersthat can be used in the present invention may further comprise any ofthe following polynucleotides (k) to (o):

(k) a polynucleotide consisting of a nucleotide sequence represented byany of SEQ ID NOs: 349 to 383 or a nucleotide sequence derived from thenucleotide sequence by the replacement of u with t, a variant thereof, aderivative thereof, or a fragment thereof comprising 15 or moreconsecutive nucleotides;(l) a polynucleotide comprising a nucleotide sequence represented by anyof SEQ ID NOs: 349 to 383;(m) a polynucleotide consisting of a nucleotide sequence complementaryto a nucleotide sequence represented by any of SEQ ID NOs: 349 to 383 ora nucleotide sequence derived from the nucleotide sequence by thereplacement of u with t, a variant thereof, a derivative thereof, or afragment thereof comprising 15 or more consecutive nucleotides;(n) a polynucleotide comprising a nucleotide sequence complementary to anucleotide sequence represented by any of SEQ ID NOs: 349 to 383 or anucleotide sequence derived from the nucleotide sequence by thereplacement of u with t; and(o) a polynucleotide hybridizing under stringent conditions to any ofthe polynucleotides (k) to (n).

For the above-mentioned polynucleotides, the “fragment thereofcomprising 15 or more consecutive nucleotides” can comprise, but is notlimited to, the number of nucleotides in the range of, for example, from15 consecutive nucleotides to less than the total number of nucleotidesof the sequence, from 17 consecutive nucleotides to less than the totalnumber of nucleotides of the sequence, from 19 consecutive nucleotidesto less than the total number of nucleotides of the sequence, or thelike, and is from the nucleotide sequence of each polynucleotide.

These polynucleotides or fragments thereof used in the present inventionmay each be DNA or may each be RNA.

The polynucleotides that can be used in the present invention can beprepared by use of a general technique such as a DNA recombinationtechnique, a PCR method, or a method using an automatic DNA/RNAsynthesizer.

The DNA recombination technique and the PCR method may employ techniquesdescribed in, for example, Ausubel et al., Current Protocols inMolecular Biology, John Willey & Sons, US (1993); and Sambrook et al.,Molecular Cloning—A Laboratory Manual, Cold Spring Harbor LaboratoryPress, US (1989).

The human-derived hsa-miR-6893-5p, hsa-miR-6075, hsa-miR-6820-5p,hsa-miR-4294, hsa-miR-6729-5p, hsa-miR-4476, hsa-miR-6836-3p,hsa-miR-6765-3p, hsa-miR-6799-5p, hsa-miR-4530, hsa-miR-7641,hsa-miR-4454, hsa-miR-615-5p, hsa-miR-8073, hsa-miR-663a, hsa-miR-4634,hsa-miR-4450, hsa-miR-4792, hsa-miR-665, hsa-miR-7975, hsa-miR-7109-5p,hsa-miR-6789-5p, hsa-miR-4497, hsa-miR-6877-5p, hsa-miR-6880-5p,hsa-miR-7977, hsa-miR-4734, hsa-miR-6821-5p, hsa-miR-8089,hsa-miR-5585-3p, hsa-miR-6085, hsa-miR-6845-5p, hsa-miR-4651,hsa-miR-4433-3p, hsa-miR-1231, hsa-miR-4665-5p, hsa-miR-7114-5p,hsa-miR-1238-5p, hsa-miR-8069, hsa-miR-4732-5p, hsa-miR-619-5p,hsa-miR-3622a-5p, hsa-miR-1260a, hsa-miR-6741-5p, hsa-miR-6781-5p,hsa-miR-6125, hsa-miR-6805-5p, hsa-miR-6132, hsa-miR-6872-3p,hsa-miR-6875-5p, hsa-miR-1908-3p, hsa-miR-4433b-3p, hsa-miR-4736,hsa-miR-5100, hsa-miR-6724-5p, hsa-miR-7107-5p, hsa-miR-6726-5p,hsa-miR-3185, hsa-miR-4638-5p, hsa-miR-1273g-3p, hsa-miR-6778-5p,hsa-miR-328-5p, hsa-miR-3679-3p, hsa-miR-1228-3p, hsa-miR-6779-5p,hsa-miR-4723-5p, hsa-miR-6850-5p, hsa-miR-760, hsa-miR-7704,hsa-miR-8072, hsa-miR-4486, hsa-miR-1913, hsa-miR-4656, hsa-miR-1260b,hsa-miR-7106-5p, hsa-miR-6889-5p, hsa-miR-6780b-5p, hsa-miR-6090,hsa-miR-4534, hsa-miR-4449, hsa-miR-5195-3p, hsa-miR-1202, hsa-miR-4467,hsa-miR-6515-3p, hsa-miR-4281, hsa-miR-4505, hsa-miR-4484,hsa-miR-6805-3p, hsa-miR-3135b, hsa-miR-3162-5p, hsa-miR-6768-5p,hsa-miR-6721-5p, hsa-miR-1227-5p, hsa-miR-6722-3p, hsa-miR-4286,hsa-miR-4746-3p, hsa-miR-6727-5p, hsa-miR-6816-5p, hsa-miR-4741,hsa-miR-4508, hsa-miR-940, hsa-miR-4327, hsa-miR-4665-3p, hsa-miR-718,hsa-miR-125a-3p, hsa-miR-204-3p, hsa-miR-1469, hsa-miR-575,hsa-miR-150-3p, hsa-miR-423-5p, hsa-miR-564, hsa-miR-3188, hsa-miR-1246,hsa-miR-602, hsa-miR-1290, hsa-miR-16-5p, hsa-miR-451 a, hsa-miR-24-3p,hsa-miR-187-5p, hsa-miR-1908-5p, hsa-miR-371 a-5p, hsa-miR-550a-5p,hsa-miR-4417, hsa-miR-4707-5p, hsa-miR-7847-3p, hsa-miR-2861,hsa-miR-4513, hsa-miR-7111-5p, hsa-miR-6777-5p, hsa-miR-7113-3p,hsa-miR-4648, hsa-miR-3184-5p, hsa-miR-4271, hsa-miR-6791-5p,hsa-miR-642a-3p, hsa-miR-7108-5p, hsa-miR-128-1-5p, hsa-miR-5196-5p,hsa-miR-3178, hsa-miR-3656, hsa-miR-92a-2-5p, hsa-miR-6769b-5p,hsa-miR-4689, hsa-miR-6076, hsa-miR-92b-5p, hsa-miR-6774-5p,hsa-miR-486-3p, hsa-miR-6806-5p, hsa-miR-6842-5p, hsa-miR-6716-5p,hsa-miR-557, hsa-miR-4673, hsa-miR-4674, hsa-miR-4442, hsa-miR-1915-3p,hsa-miR-4687-3p, hsa-miR-92b-3p, hsa-miR-1203, hsa-miR-663b,hsa-miR-4258, hsa-miR-4649-5p, hsa-miR-4516, hsa-miR-3619-3p,hsa-miR-6826-5p, hsa-miR-6757-5p, hsa-miR-3131, hsa-miR-1343-3p,hsa-miR-6775-5p, hsa-miR-6813-5p and hsa-miR-3940-5p represented by SEQID NOs: 1 to 122, 349 to 383, 464 to 473, and 492 to 494 are known inthe art, and their obtainment methods are also known as mentioned above.Therefore, each polynucleotide that can be used as a nucleic acid probeor a primer in the present invention can be prepared by cloning thegene.

Such nucleic acid probes or primers can be chemically synthesized usingan automatic DNA synthesizer. In general, the phosphoramidite method isused in this synthesis, and single-stranded DNA up to approximately 100nucleotides can be automatically synthesized by this method. Theautomatic DNA synthesizer is commercially available from, for example,Polygen GmbH, ABI, or Applied Biosystems, Inc.

Alternatively, the polynucleotides of the present invention can also beprepared by cDNA cloning methods. The cDNA cloning technique may employ,for example, microRNA Cloning Kit Wako.

In this context, the sequences of the nucleic acid probes and theprimers for detecting the polynucleotide consisting of a nucleotidesequence represented by any of SEQ ID NOs: 1 to 122, 349 to 383, 464 to473, and 492 to 494 do not exist as miRNAs or precursors thereof in theliving body or in vivo. For example, the nucleotide sequencesrepresented by SEQ ID NO: 36 and SEQ ID NO: 103 are produced from theprecursor represented by SEQ ID NO: 159. This precursor has ahairpin-like structure as shown in FIG. 1, and the nucleotide sequencesrepresented by SEQ ID NO: 36 and SEQ ID NO: 103 have mismatch sequenceswith each other. As such, a nucleotide sequence completely complementaryto the nucleotide sequence represented by SEQ ID NO: 36 or SEQ ID NO:103 does not naturally occur in vivo. Therefore, the nucleic acid probesand the primers for detecting the nucleotide sequence represented by anyof SEQ ID NOs: 1 to 122, 349 to 383, 464 to 473, and 492 to 494 haveartificial nucleotide sequences that do not exist in the living body orin vivo.

3. Kit or Device for Detection of Pancreatic Cancer

The present invention also provides a kit or a device for the detectionof pancreatic cancer, comprising one or more polynucleotides (which mayinclude a variant, a fragment, or a derivative thereof) that can be usedas nucleic acid probes or primers in the present invention for measuringtarget nucleic acids as pancreatic cancer markers.

The target nucleic acids as pancreatic cancer markers according to thepresent invention are at least one nucleic acid selected from thefollowing group A:

Group A:

miR-6893-5p, miR-6075, miR-6820-5p, miR-4294, miR-6729-5p, miR-4476,miR-6836-3p, miR-6765-3p, miR-6799-5p, miR-4530, miR-7641, miR-4454,miR-615-5p, miR-8073, miR-663a, miR-4634, miR-4450, miR-4792, miR-665,miR-7975, miR-7109-5p, miR-6789-5p, miR-4497, miR-6877-5p, miR-6880-5p,miR-7977, miR-4734, miR-6821-5p, miR-8089, miR-5585-3p, miR-6085,miR-6845-5p, miR-4651, miR-4433-3p, miR-1231, miR-4665-5p, miR-7114-5p,miR-1238-5p, miR-8069, miR-4732-5p, miR-619-5p, miR-3622a-5p, miR-1260a,miR-6741-5p, miR-6781-5p, miR-6125, miR-6805-5p, miR-6132, miR-6872-3p,miR-6875-5p, miR-1908-3p, miR-4433b-3p, miR-4736, miR-5100, miR-6724-5p,miR-7107-5p, miR-6726-5p, miR-3185, miR-4638-5p, miR-1273g-3p,miR-6778-5p, miR-328-5p, miR-3679-3p, miR-1228-3p, miR-6779-5p,miR-4723-5p, miR-6850-5p, miR-760, miR-7704, miR-8072, miR-4486,miR-1913, miR-4656, miR-1260b, miR-7106-5p, miR-6889-5p, miR-6780b-5p,miR-6090, miR-4534, miR-4449, miR-5195-3p, miR-1202, miR-4467,miR-6515-3p, miR-4281, miR-4505, miR-4484, miR-6805-3p, miR-3135b,miR-3162-5p, miR-6768-5p, miR-6721-5p, miR-1227-5p, miR-6722-3p,miR-4286, miR-4746-3p, miR-6727-5p, miR-6816-5p, miR-4741, miR-4508,miR-940, miR-4327, miR-4665-3p, miR-718, miR-1203, miR-663b, miR-4258,miR-4649-5p, miR-4516, miR-3619-3p, miR-6826-5p, miR-6757-5p, miR-3131,miR-1343-3p, miR-6775-5p, miR-6813-5p, and miR-3940-5p.

Additional target nucleic acids that may be optionally used in themeasurement are at least one nucleic acid selected from the followinggroup B:

Group B:

miR-125a-3p, miR-204-3p, miR-1469, miR-575, miR-150-3p, miR-423-5p,miR-564, miR-3188, miR-1246, miR-602, miR-1290, miR-16-5p, miR-451a,miR-24-3p, miR-187-5p, miR-1908-5p, miR-371a-5p, and miR-550a-5p.

Additional target nucleic acids that may be further optionally used inthe measurement are at least one nucleic acid selected from thefollowing group C:

Group C:

miR-4417, miR-4707-5p, miR-7847-3p, miR-2861, miR-4513, miR-7111-5p,miR-6777-5p, miR-7113-3p, miR-4648, miR-3184-5p, miR-4271, miR-6791-5p,miR-642a-3p, miR-7108-5p, miR-128-1-5p, miR-5196-5p, miR-3178, miR-3656,miR-92a-2-5p, miR-6769b-5p, miR-4689, miR-6076, miR-92b-5p, miR-6774-5p,miR-486-3p, miR-6806-5p, miR-6842-5p, miR-6716-5p, miR-557, miR-4673,miR-4674, miR-4442, miR-1915-3p, miR-4687-3p, and miR-92b-3p.

The kit or the device of the present invention comprises one or morenucleic acids capable of specifically binding to any of the targetnucleic acids as the pancreatic cancer markers described above,preferably one or more polynucleotides selected from the polynucleotidesdescribed in the preceding Section 2, or variants thereof.

Specifically, the kit or the device of the present invention cancomprise at least one or more polynucleotides comprising (or consistingof) a nucleotide sequence represented by any of SEQ ID NOs: 1 to 104,464 to 473, and 492 to 494 or a nucleotide sequence derived from thenucleotide sequence by the replacement of u with t, polynucleotide(s)comprising (or consisting of) a complementary sequence thereof, apolynucleotide(s) hybridizing under stringent conditions to any of thesepolynucleotides, or a variant(s) or a fragment(s) comprising 15 or moreconsecutive nucleotides of any of these polynucleotide sequences.

The kit or the device of the present invention can further comprise oneor more polynucleotides comprising (or consisting of) a nucleotidesequence represented by any of SEQ ID NOs: 105 to 122 or a nucleotidesequence derived from the nucleotide sequence by the replacement of uwith t, a polynucleotide(s) comprising (or consisting of) acomplementary sequence thereof, a polynucleotide(s) hybridizing understringent conditions to any of these polynucleotides, a variant(s) or afragment(s) comprising 15 or more consecutive nucleotides of any ofthese polynucleotide sequences.

The kit or the device of the present invention can further comprise oneor more polynucleotides comprising (or consisting of) a nucleotidesequence represented by any of SEQ ID NOs: 349 to 383 or a nucleotidesequence derived from the nucleotide sequence by the replacement of uwith t, polynucleotide(s) comprising (or consisting of) a complementarysequence thereof, a polynucleotide(s) hybridizing under stringentconditions to any of these polynucleotides, a variant(s) or afragment(s) comprising 15 or more consecutive nucleotides of any ofthese polynucleotide sequences.

The fragment or fragments that can be comprised in the kit or the deviceof the present invention is/are, for example, one or morepolynucleotides, preferably two or more polynucleotides, selected fromthe group consisting of the following polynucleotides (1) to (3):

(1) a polynucleotide comprising 15 or more consecutive nucleotides thatare from a nucleotide sequence derived from a nucleotide sequencerepresented by any of SEQ ID NOs: 1 to 104, 464 to 473, and 492 to 494by the replacement of u with t, or a complementary sequence thereof;(2) a polynucleotide comprising 15 or more consecutive nucleotides thatare from a nucleotide sequence derived from a nucleotide sequencerepresented by any of SEQ ID NOs: 105 to 122 by the replacement of uwith t, or a complementary sequence thereof; and(3) a polynucleotide comprising 15 or more consecutive nucleotides thatare from a nucleotide sequence derived from a nucleotide sequencerepresented by any of SEQ ID NOs: 349 to 383 by the replacement of uwith t, or a complementary sequence thereof.

In a preferred embodiment, the polynucleotide is a polynucleotideconsisting of a nucleotide sequence represented by any of SEQ ID NOs: 1to 104, 464 to 473, and 492 to 494 or a nucleotide sequence derived fromthe nucleotide sequence by the replacement of u with t, a polynucleotideconsisting of a complementary sequence thereof, a polynucleotidehybridizing under stringent conditions to any of these polynucleotides,or a variant thereof comprising 15 or more, preferably 17 or more, morepreferably 19 or more consecutive nucleotides.

In a preferred embodiment, the polynucleotide is a polynucleotideconsisting of a nucleotide sequence represented by any of SEQ ID NOs:105 to 122 or a nucleotide sequence derived from the nucleotide sequenceby the replacement of u with t, a polynucleotide consisting of acomplementary sequence thereof, a polynucleotide hybridizing understringent conditions to any of these polynucleotides, or a variantthereof comprising 15 or more, preferably 17 or more, more preferably 19or more consecutive nucleotides.

In a preferred embodiment, the polynucleotide is a polynucleotideconsisting of a nucleotide sequence represented by any of SEQ ID NOs:349 to 383 or a nucleotide sequence derived from the nucleotide sequenceby the replacement of u with t, a polynucleotide consisting of acomplementary sequence thereof, a polynucleotide hybridizing understringent conditions to any of these polynucleotides, or a variantthereof comprising 15 or more, preferably 17 or more, more preferably 19or more consecutive nucleotides.

In a preferred embodiment, the fragment can be a polynucleotidecomprising 15 or more, preferably 17 or more, more preferably 19 or moreconsecutive nucleotides.

In the present invention, the size of the polynucleotide fragment is thenumber of nucleotides in the range from, for example, 15 consecutivenucleotides to less than the total number of nucleotides of thesequence, from 17 consecutive nucleotides to less than the total numberof nucleotides of the sequence, or from 19 consecutive nucleotides toless than the total number of nucleotides of the sequence, in thenucleotide sequence of each polynucleotide.

Specific examples of the aforementioned combination constituting the kitor the device of the present invention can include the above-mentionedpolynucleotides relevant to the combinations of SEQ ID NOs shown inTable 1 (i.e., SEQ ID NOs: 1 to 122, 349 to 383, 464 to 473, and 492 to494 corresponding to the miRNA markers in Table 1). However, these aregiven merely for illustrative purposes, and all of various otherpossible combinations are included in the present invention.

The combination constituting the kit or the device for discriminating apancreatic cancer patient from a healthy subject according to thepresent invention is desirably, for example, a combination of two ormore polynucleotides consisting of the nucleotide sequences representedby SEQ ID NOs shown in Table 1. Usually, a combination of two of thesepolynucleotides can produce adequate performance.

The specific combination of two polynucleotides that consist of theabove-mentioned nucleotide sequences or the complementary sequencesthereof for discriminating a pancreatic cancer patient from a healthysubject is preferably a combination comprising at least one or morepolynucleotides of the newly found polynucleotides consisting of thenucleotide sequences represented by SEQ ID NOs: 1 to 104, 349 to 383,464 to 473, and 492 to 494, among the combinations constituted by twopolynucleotides of the polynucleotides consisting of the nucleotidesequences represented by SEQ ID NOs: 1 to 122, 349 to 383, 464 to 473,and 492 to 494.

The combination of two polynucleotides that consist of theabove-mentioned nucleotide sequences or the complementary sequencesthereof for discriminating a pancreatic cancer patient from a healthysubject is preferably a combination of two polynucleotides comprising atleast one polynucleotide selected from the group consisting ofpolynucleotides consisting of the nucleotide sequences represented bySEQ ID NOs: 1, 2, 4, 7, 15, 24, 105, 107, and 108 or complementarysequences thereof, with any of the polynucleotides of the other SEQ IDNOs.

Non-limiting examples of the combination comprising a polynucleotideconsisting of the nucleotide sequence represented by SEQ ID NO: 1 or acomplementary sequence thereof among the combinations constituted by twopolynucleotides of the polynucleotides consisting of the nucleotidesequences represented by SEQ ID NOs: 1 to 122, 349 to 383, 464 to 473,and 492 to 494 for discriminating a pancreatic cancer patient from ahealthy subject are listed below:

(1) a combination of SEQ ID NOs: 1 and 77 (markers: hsa-miR-6893-5p andhsa-miR-6780b-5p);

(2) a combination of SEQ ID NOs: 1 and 119 (markers: hsa-miR-6893-5p andhsa-miR-187-5p); and

(3) a combination of SEQ ID NOs: 1 and 20 (markers: hsa-miR-6893-5p andhsa-miR-7975).

Non-limiting examples of the combination comprising a polynucleotideconsisting of the nucleotide sequence represented by SEQ ID NO: 2 or acomplementary sequence thereof among the combinations constituted by twopolynucleotides of the polynucleotides consisting of the nucleotidesequences represented by SEQ ID NOs: 1 to 122, 349 to 383, 464 to 473,and 492 to 494 for discriminating a pancreatic cancer patient from ahealthy subject are further listed below:

(1) a combination of SEQ ID NOs: 2 and 105 (markers: hsa-miR-6075 andhsa-miR-125a-3p);

(2) a combination of SEQ ID NOs: 2 and 16 (markers: hsa-miR-6075 andhsa-miR-4634); and

(3) a combination of SEQ ID NOs: 2 and 10 (markers: hsa-miR-6075 andhsa-miR-4530).

Non-limiting examples of the combination comprising a polynucleotideconsisting of the nucleotide sequence represented by SEQ ID NO: 4 or acomplementary sequence thereof among the combinations constituted by twopolynucleotides of the polynucleotides consisting of the nucleotidesequences represented by SEQ ID NOs: 1 to 122, 349 to 383, 464 to 473,and 492 to 494 for discriminating a pancreatic cancer patient from ahealthy subject are further listed below:

(1) a combination of SEQ ID NOs: 4 and 105 (markers: hsa-miR-4294 andhsa-miR-125a-3p);

(2) a combination of SEQ ID NOs: 4 and 119 (markers: hsa-miR-4294 andhsa-miR-187-5p); and

(3) a combination of SEQ ID NOs: 4 and 45 (markers: hsa-miR-4294 andhsa-miR-6781-5p).

Non-limiting examples of the combination comprising a polynucleotideconsisting of the nucleotide sequence represented by SEQ ID NO: 7 or acomplementary sequence thereof among the combinations constituted by twopolynucleotides of the polynucleotides consisting of the nucleotidesequences represented by SEQ ID NOs: 1 to 122, 349 to 383, 464 to 473,and 492 to 494 for discriminating a pancreatic cancer patient from ahealthy subject are further listed below:

(1) a combination of SEQ ID NOs: 7 and 105 (markers: hsa-miR-6836-3p andhsa-miR-125a-3p);

(2) a combination of SEQ ID NOs: 7 and 34 (markers: hsa-miR-6836-3p andhsa-miR-4433-3p); and

(3) a combination of SEQ ID NOs: 7 and 12 (markers: hsa-miR-6836-3p andhsa-miR-4454).

Non-limiting examples of the combination comprising a polynucleotideconsisting of the nucleotide sequence represented by SEQ ID NO: 105 or acomplementary sequence thereof among the combinations constituted by twopolynucleotides of the polynucleotides consisting of the nucleotidesequences represented by SEQ ID NOs: 1 to 122, 349 to 383, 464 to 473,and 492 to 494 for discriminating a pancreatic cancer patient from ahealthy subject are further listed below:

(1) a combination of SEQ ID NOs: 18 and 105 (markers: hsa-miR-4792 andhsa-miR-125a-3p);

(2) a combination of SEQ ID NOs: 46 and 105 (markers: hsa-miR-6125 andhsa-miR-125a-3p); and

(3) a combination of SEQ ID NOs: 105 and 494 (markers: hsa-miR-125a-3pand hsa-miR-3940-5p).

The combination of polynucleotides with cancer type specificity capableof discriminating a pancreatic cancer patient not only from a healthysubject but also from other cancer patients is preferably, for example,a combination of multiple polynucleotides comprising: at least onepolynucleotide selected from the group consisting of polynucleotidesconsisting of the nucleotide sequences represented by SEQ ID NOs: 2, 4,6, 7, 9, 10, 25, 28, 30, 31, 38, 48, 82, 103, 105, 108, and 464 orcomplementary sequences thereof (hereinafter, this group is referred toas “cancer type-specific polynucleotide group 1”); and any of thepolynucleotides of the other SEQ ID NOs.

The combination of polynucleotides with cancer type specificity capableof discriminating a pancreatic cancer patient not only from a healthysubject but also from other cancer patients is more preferably acombination of multiple polynucleotides selected from the cancertype-specific polynucleotide group 1.

The combination of polynucleotides with cancer type specificity capableof discriminating a pancreatic cancer patient not only from a healthysubject but also from other cancer patients is more preferably acombination comprising at least one or more polynucleotides selectedfrom the group consisting of polynucleotides consisting of thenucleotide sequences represented by SEQ ID NOs: 2, 4, 7, 10, and 25 orcomplementary sequences thereof (hereinafter, this group is referred toas “cancer type-specific polynucleotide group 2”) included in the cancertype-specific polynucleotide group 1, among the combinations of multiplepolynucleotides selected from the cancer type-specific polynucleotidegroup 1. The number of the polynucleotides with cancer type specificitymay be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more in the combination and ismore preferably 4 or more in the combination. Usually, the combinationof 4 polynucleotides of these polynucleotides can produce adequateperformance.

Non-limiting examples of the combination of the polynucleotideconsisting of the nucleotide sequence represented by SEQ ID NO: 2 or acomplementary sequence thereof, with polynucleotides consisting ofnucleotide sequences represented by SEQ ID NOs of three polynucleotidesselected from the cancer type-specific polynucleotide group 1 orcomplementary sequences thereof are listed below:

(1) a combination of SEQ ID NOs: 2, 9, 105, and 7 (markers:hsa-miR-6075, hsa-miR-6799-5p, hsa-miR-125a-3p, and hsa-miR-6836-3p);

(2) a combination of SEQ ID NOs: 2, 7, 108, and 464 (markers:hsa-miR-6075, hsa-miR-6836-3p, hsa-miR-575, and hsa-miR-1203);

(3) a combination of SEQ ID NOs: 2, 31, 48, and 38 (markers:hsa-miR-6075, hsa-miR-6085, hsa-miR-6132, and hsa-miR-1238-5p);

(4) a combination of SEQ ID NOs: 2, 31, 28, and 48 (markers:hsa-miR-6075, hsa-miR-6085, hsa-miR-6821-5p, and hsa-miR-6132); and

(5) a combination of SEQ ID NOs: 2, 25, 105, and 10 (markers:hsa-miR-6075, hsa-miR-6880-5p, hsa-miR-125a-3p, and hsa-miR-4530).

Non-limiting examples of the combination of the polynucleotideconsisting of the nucleotide sequence represented by SEQ ID NO: 4 or acomplementary sequence thereof, with polynucleotides consisting ofnucleotide sequences represented by SEQ ID NOs of three polynucleotidesselected from the cancer type-specific polynucleotide group 1 orcomplementary sequences thereof are further listed below:

(1) a combination of SEQ ID NOs: 4, 31, 7, and 82 (markers:hsa-miR-4294, hsa-miR-6085, hsa-miR-6836-3p, and hsa-miR-1202);

(2) a combination of SEQ ID NOs: 4, 31, 28, and 82 (markers:hsa-miR-4294, hsa-miR-6085, hsa-miR-6821-5p, and hsa-miR-1202);

(3) a combination of SEQ ID NOs: 4, 10, 7, and 82 (markers:hsa-miR-4294, hsa-miR-4530, hsa-miR-6836-3p, and hsa-miR-1202);

(4) a combination of SEQ ID NOs: 4, 7, 82, and 103 (markers:hsa-miR-4294, hsa-miR-6836-3p, hsa-miR-1202, and hsa-miR-4665-3p); and

(5) a combination of SEQ ID NOs: 4, 105, 10, and 6 (markers:hsa-miR-4294, hsa-miR-125a-3p, hsa-miR-4530, and hsa-miR-4476).

Non-limiting examples of the combination of the polynucleotideconsisting of the nucleotide sequence represented by SEQ ID NO: 7 or acomplementary sequence thereof, with polynucleotides consisting ofnucleotide sequences represented by SEQ ID NOs of three polynucleotidesselected from the cancer type-specific polynucleotide group 1 orcomplementary sequences thereof are further listed below:

(1) a combination of SEQ ID NOs: 4, 7, 82, and 101 (markers:hsa-miR-4294, hsa-miR-6836-3p, hsa-miR-1202, and hsa-miR-940);

(2) a combination of SEQ ID NOs: 4, 7, 38, and 82 (markers:hsa-miR-4294, hsa-miR-6836-3p, hsa-miR-1238-5p, and hsa-miR-1202);

(3) a combination of SEQ ID NOs: 6, 7, 61, and 68 (markers:hsa-miR-4476, hsa-miR-6836-3p, hsa-miR-6778-5p, and hsa-miR-760);

(4) a combination of SEQ ID NOs: 4, 7, 47, and 82 (markers:hsa-miR-4294, hsa-miR-6836-3p, hsa-miR-6805-5p, and hsa-miR-1202); and

(5) a combination of SEQ ID NOs: 4, 7, 82, and 103 (markers:hsa-miR-4294, hsa-miR-6836-3p, hsa-miR-1202, and hsa-miR-4665-3p).

Non-limiting examples of the combination of the polynucleotideconsisting of the nucleotide sequence represented by SEQ ID NO: 10 or acomplementary sequence thereof, with polynucleotides consisting ofnucleotide sequences represented by SEQ ID NOs of three polynucleotidesselected from the cancer type-specific polynucleotide group 1 orcomplementary sequences thereof are further listed below:

(1) a combination of SEQ ID NOs: 10, 47, 90, and 101 (markers:hsa-miR-4530, hsa-miR-6805-5p, hsa-miR-3162-5p, and hsa-miR-940);

(2) a combination of SEQ ID NOs: 10, 30, 103, and 365 (markers:hsa-miR-4530, hsa-miR-5585-3p, hsa-miR-4665-3p, and hsa-miR-3178);

(3) a combination of SEQ ID NOs: 9, 10, 61, and 68 (markers:hsa-miR-6799-5p, hsa-miR-4530, hsa-miR-6778-5p, and hsa-miR-760);

(4) a combination of SEQ ID NOs: 10, 48, 68, and 90 (markers:hsa-miR-4530, hsa-miR-6132, hsa-miR-760, and hsa-miR-3162-5p); and

(5) a combination of SEQ ID NOs: 10, 30, 68, and 365 (markers:hsa-miR-4530, hsa-miR-5585-3p, hsa-miR-760, and hsa-miR-3178).

Non-limiting examples of the combination of the polynucleotideconsisting of the nucleotide sequence represented by SEQ ID NO: 25 or acomplementary sequence thereof, with polynucleotides consisting ofnucleotide sequences represented by SEQ ID NOs of three polynucleotidesselected from the cancer type-specific polynucleotide group 1 orcomplementary sequences thereof are further listed below:

(1) a combination of SEQ ID NOs: 7, 25, 466, and 47 (markers:hsa-miR-6836-3p, hsa-miR-6880-5p, hsa-miR-4258, and hsa-miR-6805-5p);

(2) a combination of SEQ ID NOs: 7, 25, 48, and 466 (markers:hsa-miR-6836-3p, hsa-miR-6880-5p, hsa-miR-6132, and hsa-miR-4258);

(3) a combination of SEQ ID NOs: 7, 25, 28, and 466 (markers:hsa-miR-6836-3p, hsa-miR-6880-5p, hsa-miR-6821-5p, and hsa-miR-4258);

(4) a combination of SEQ ID NOs: 7, 25, 30, and 466 (markers:hsa-miR-6836-3p, hsa-miR-6880-5p, hsa-miR-5585-3p, and hsa-miR-4258);and

(5) a combination of SEQ ID NOs: 7, 25, 31, and 47 (markers:hsa-miR-6836-3p, hsa-miR-6880-5p, hsa-miR-6085, and hsa-miR-6805-5p).

The kit or the device of the present invention can also comprise a knownpolynucleotide(s) that enables detection of pancreatic cancer, or apolynucleotide(s) that will be found in the future, in addition to thepolynucleotide(s) (which may include a variant(s), a fragment(s), and aderivative(s)) as described above according to the present invention.

The kit of the present invention can also comprise an antibody formeasuring a marker or markers for pancreatic cancer examination known inthe art, such as CEA, CA19-9, SPan-1, DUPAN-2, CA50, CA242, TAG-72,urinary fucose, POA, and TPS, in addition to the polynucleotide(s)according to the present invention as described above, and a variant orvariants thereof or a fragment or fragments thereof.

These polynucleotides and variants thereof or fragments thereofcontained in the kit of the present invention may be packaged indifferent containers either individually or in any combination.

The kit of the present invention may comprise a kit for extractingnucleic acids (e.g., total RNA) from body fluids, cells, or tissues, afluorescent material for labeling, an enzyme and a medium for nucleicacid amplification, an instruction manual, etc.

The device of the present invention is a device for cancer markermeasurement in which nucleic acids such as the polynucleotides accordingto the present invention described above, variants thereof, derivativesthereof, or fragments thereof are bonded or attached to, for example, asolid phase. Examples of the material for the solid phase includeplastics, paper, glass, and silicon. The material for the solid phase ispreferably a plastic from the viewpoint of easy processability. Thesolid phase has any shape and is, for example, square, round,reed-shaped, or film-shaped. The device of the present inventionincludes, for example, a device for measurement by a hybridizationtechnique. Specific examples thereof include blotting devices andnucleic acid arrays (e.g., microarrays, DNA chips, and RNA chips).

The nucleic acid array technique is a technique which involves bondingor attaching the nucleic acids one by one by use of a method [e.g., amethod of spotting the nucleic acids using a high-density dispensercalled spotter or arrayer onto the surface of the solid phasesurface-treated, if necessary, by coating with L-lysine or theintroduction of a functional group such as an amino group or a carboxylgroup, a method of spraying the nucleic acids onto the solid phase usingan inkjet which injects very small liquid droplets by a piezoelectricelement or the like from a nozzle, or a method of sequentiallysynthesizing nucleotides on the solid phase] to prepare an array such asa chip and measuring target nucleic acids through the use ofhybridization using this array.

The kit or the device of the present invention comprises nucleic acidscapable of specifically binding to the polynucleotides of at least oneor more, preferably at least two or more, more preferably at least threeor more, most preferably at least five or more to all of the pancreaticcancer marker miRNAs, respectively, of the group 1 described above. Thekit or the device of the present invention can optionally furthercomprise nucleic acids capable of specifically binding to thepolynucleotides of at least one or more, preferably at least two ormore, more preferably at least three or more, most preferably at leastfive or more to all of the pancreatic cancer marker miRNAs,respectively, of the group 2 described above. The kit or the device ofthe present invention can optionally further comprise nucleic acidscapable of specifically binding to the polynucleotides of at least oneor more, preferably at least two or more, more preferably at least threeor more, most preferably at least five or more to all of the pancreaticcancer marker miRNAs, respectively, of the group 3 described above.

The kit or the device of the present invention can be used for detectingpancreatic cancer as described in Section 4 below.

4. Method for Detecting Pancreatic Cancer

The present invention further provides a method for detecting pancreaticcancer, comprising using the kit or the device of the present invention(comprising the above-mentioned nucleic acid(s) that can be used in thepresent invention) as described in Section 3 above to measure expressionlevels of one or more pancreatic cancer-derived genes represented by: anexpression level(s) of pancreatic cancer-derived gene(s) selected fromthe following group of miRNAs, i.e., miR-6893-5p, miR-6075, miR-6820-5p,miR-4294, miR-6729-5p, miR-4476, miR-6836-3p, miR-6765-3p, miR-6799-5p,miR-4530, miR-7641, miR-4454, miR-615-5p, miR-8073, miR-663a, miR-4634,miR-4450, miR-4792, miR-665, miR-7975, miR-7109-5p, miR-6789-5p,miR-4497, miR-6877-5p, miR-6880-5p, miR-7977, miR-4734, miR-6821-5p,miR-8089, miR-5585-3p, miR-6085, miR-6845-5p, miR-4651, miR-4433-3p,miR-1231, miR-4665-5p, miR-7114-5p, miR-1238-5p, miR-8069, miR-4732-5p,miR-619-5p, miR-3622a-5p, miR-1260a, miR-6741-5p, miR-6781-5p, miR-6125,miR-6805-5p, miR-6132, miR-6872-3p, miR-6875-5p, miR-1908-3p,miR-4433b-3p, miR-4736, miR-5100, miR-6724-5p, miR-7107-5p, miR-6726-5p,miR-3185, miR-4638-5p, miR-1273g-3p, miR-6778-5p, miR-328-5p,miR-3679-3p, miR-1228-3p, miR-6779-5p, miR-4723-5p, miR-6850-5p,miR-760, miR-7704, miR-8072, miR-4486, miR-1913, miR-4656, miR-1260b,miR-7106-5p, miR-6889-5p, miR-6780b-5p, miR-6090, miR-4534, miR-4449,miR-5195-3p, miR-1202, miR-4467, miR-6515-3p, miR-4281, miR-4505,miR-4484, miR-6805-3p, miR-3135b, miR-3162-5p, miR-6768-5p, miR-6721-5p,miR-1227-5p, miR-6722-3p, miR-4286, miR-4746-3p, miR-6727-5p,miR-6816-5p, miR-4741, miR-4508, miR-940, miR-4327, miR-4665-3p andmiR-718, miR-1203, miR-663b, miR-4258, miR-4649-5p, miR-4516,miR-3619-3p, miR-6826-5p, miR-6757-5p, miR-3131, miR-1343-3p,miR-6775-5p, miR-6813-5p, and miR-3940-5p; and optionally an expressionlevel(s) of pancreatic cancer-derived gene(s) selected from thefollowing group of miRNA: i.e., miR-125a-3p, miR-204-3p, miR-1469,miR-575, miR-150-3p, miR-423-5p, miR-564, miR-3188, miR-1246, miR-602,miR-1290, miR-16-5p, miR-451a, miR-24-3p, miR-187-5p, miR-1908-5p,miR-371a-5p, and miR-550a-5p; and optionally an expression level(s) ofpancreatic cancer-derived gene(s) selected from the following group ofmiRNAs, i.e., miR-4417, miR-4707-5p, miR-7847-3p, miR-2861, miR-4513,miR-7111-5p, miR-6777-5p, miR-7113-3p, miR-4648, miR-3184-5p, miR-4271,miR-6791-5p, miR-642a-3p, miR-7108-5p, miR-128-1-5p, miR-5196-5p,miR-3178, miR-3656, miR-92a-2-5p, miR-6769b-5p, miR-4689, miR-6076,miR-92b-5p, miR-6774-5p, miR-486-3p, miR-6806-5p, miR-6842-5p,miR-6716-5p, miR-557, miR-4673, miR-4674, miR-4442, miR-1915-3p,miR-4687-3p, and miR-92b-3p, in a sample in vitro, further comparing,for example, the expression level(s) of the gene(s) in the sample (e.g.,blood, serum, or plasma) collected from a subject suspected of havingpancreatic cancer, with a control expression level(s) in the sample(s)collected from a healthy subject(s) (including a non-pancreatic cancerpatient(s)), and evaluating the subject as having pancreatic cancer whenthe expression level(s) of the target nucleic acid(s) is statisticallysignificantly different between the samples.

This method of the present invention enables a limitedly invasive, earlydiagnosis of the cancer with high sensitivity and high specificity andthereby brings about early treatment and improved prognosis. Inaddition, exacerbation of the disease or the effectiveness of surgical,radiotherapeutic, and chemotherapeutic treatments can be monitored.

The method for extracting the pancreatic cancer-derived gene(s) from thesample such as blood, serum, or plasma according to the presentinvention is particularly preferably prepared by the addition of areagent for RNA extraction in 3D-Gene™ RNA extraction reagent fromliquid sample kit (Toray Industries, Inc.). A general acidic phenolmethod (acid guanidinium-phenol-chloroform (AGPC)) may be used, orTrizol™ (Life Technologies Corp.) may be used. The pancreaticcancer-derived gene(s) may be prepared by the addition of a reagent forRNA extraction containing acidic phenol, such as Trizol (LifeTechnologies Corp.) or Isogen (Nippon Gene Co., Ltd., Japan).Alternatively, a kit such as miRNeasy™ Mini Kit (Qiagen N.V.) may beused, though the method is not limited thereto.

The present invention also provides use of the kit or the device of thepresent invention for detecting in vitro an expression product(s) of apancreatic cancer-derived miRNA gene(s) in a sample derived from asubject.

In the method of the present invention, the kit or the device describedabove comprises a single polynucleotide or any possible combination ofpolynucleotides that can be used in the present invention as describedabove.

In the detection or (genetic) diagnosis of pancreatic cancer accordingto the present invention, each polynucleotide contained in the kit orthe device of the present invention can be used as a probe or a primer.In the case of using the polynucleotide as a primer, TaqMan™ MicroRNAAssays from Life Technologies Corp., miScript PCR System from QiagenN.V., or the like can be used, though the method is not limited thereto.

The polynucleotide contained in the kit or the device of the presentinvention can be used as a primer or a probe according to a routinemethod in a method known in the art for specifically detecting theparticular gene, for example, a hybridization technique such as Northernblot, Southern blot, in situ hybridization, Northern hybridization, orSouthern hybridization, or a quantitative amplification technique suchas quantitative RT-PCR. A body fluid such as blood, serum, plasma, orurine from a subject is collected as a sample to be assayed according tothe type of the detection method used. Alternatively, total RNA preparedfrom such a body fluid by the method described above may be used, andvarious polynucleotides including cDNA prepared on the basis of the RNAmay be used.

The kit or the device of the present invention is useful for thediagnosis of pancreatic cancer or the detection of the presence orabsence of pancreatic cancer. Specifically, the detection of pancreaticcancer using the kit or the device can be performed by detecting invitro an expression level(s) of a gene(s) using the nucleic acidprobe(s) or the primer(s) contained in the kit or the device, in asample such as blood, serum, plasma, or urine from a subject suspectedof having pancreatic cancer. The subject suspected of having pancreaticcancer can be evaluated as having pancreatic cancer when the expressionlevel(s) of a target miRNA marker(s) measured using polynucleotide(s)(including a variant(s), a fragment(s), and a derivative(s) thereof)consisting of a nucleotide sequence(s) represented by at least one ormore of SEQ ID NOs: 1 to 104, 464 to 473, and 492 to 494 or acomplementary sequence(s) thereof, and optionally a nucleotidesequence(s) represented by one or more of SEQ ID NOs: 105 to 122 or acomplementary sequence(s) thereof, and optionally a nucleotidesequence(s) represented by one or more of SEQ ID NOs: 349 to 383 or acomplementary sequence(s) thereof, in the sample such as blood, serum,plasma, or urine of the subject, has a statistically significantdifference compared to an expression level(s) thereof in the sample suchas blood, serum, or plasma, or urine of a healthy subject.

The method of the present invention can be combined with a diagnosticimaging method such as abdominal ultrasonography, CT scanning,endoscopic retrograde cholangiopancreatography, or endoscopicultrasonography. The method of the present invention is capable ofspecifically detecting pancreatic cancer and can substantiallydiscriminate pancreatic cancer from the other cancers. Particularly, forbile duct cancer, some miRNA markers for pancreatic cancer can becommonly used. However, pancreatic cancer can be discriminated from bileduct cancer by a way of determining a discriminant boundary according toa discriminant. Alternatively, pancreatic cancer can be discriminatedtherefrom by combination with an additional diagnostic method such asthe diagnostic imaging method as described above.

The method for detecting the absence of an expression product(s) of apancreatic cancer-derived gene(s) or the presence of the expressionproduct(s) of a pancreatic cancer-derived gene(s) in a sample using thekit or the device of the present invention comprises collecting a bodyfluid such as blood, serum, plasma, or urine of a subject, and measuringthe expression level(s) of the target gene(s) contained therein usingone or more polynucleotides (including a variant(s), a fragment(s), or aderivative(s)) selected from the groups of polynucleotides of thepresent invention, to evaluate the presence or absence of pancreaticcancer or to detect pancreatic cancer. The method for detectingpancreatic cancer according to the present invention can also evaluateor diagnose, for example, the presence or absence of amelioration of thedisease or the degree of amelioration thereof in a pancreatic cancerpatient in the case that a therapeutic drug is administered to thepatient for amelioration of the disease.

The method of the present invention can comprise, for example, thefollowing steps (a), (b), and (c):

(a) a step of contacting in vitro a sample from a subject with apolynucleotide(s) contained in the kit or the device of the presentinvention;

(b) a step of measuring an expression level(s) of the target nucleicacid(s) in the sample using the polynucleotide(s) as a nucleic acidprobe(s) or primer(s); and

(c) a step of evaluating the presence or absence of pancreatic cancer(cells) in the subject on the basis of the measurement results in thestep (b).

Specifically, the present invention provides a method for detectingpancreatic cancer, comprising: measuring an expression level(s) of atarget nucleic acid(s) in a sample of a subject using a nucleic acid(s)capable of specifically binding to at least one or more (preferably atleast two or more) polynucleotides selected from the following miRNAs:miR-6893-5p, miR-6075, miR-6820-5p, miR-4294, miR-6729-5p, miR-4476,miR-6836-3p, miR-6765-3p, miR-6799-5p, miR-4530, miR-7641, miR-4454,miR-615-5p, miR-8073, miR-663a, miR-4634, miR-4450, miR-4792, miR-665,miR-7975, miR-7109-5p, miR-6789-5p, miR-4497, miR-6877-5p, miR-6880-5p,miR-7977, miR-4734, miR-6821-5p, miR-8089, miR-5585-3p, miR-6085,miR-6845-5p, miR-4651, miR-4433-3p, miR-1231, miR-4665-5p, miR-7114-5p,miR-1238-5p, miR-8069, miR-4732-5p, miR-619-5p, miR-3622a-5p, miR-1260a,miR-6741-5p, miR-6781-5p, miR-6125, miR-6805-5p, miR-6132, miR-6872-3p,miR-6875-5p, miR-1908-3p, miR-4433b-3p, miR-4736, miR-5100, miR-6724-5p,miR-7107-5p, miR-6726-5p, miR-3185, miR-4638-5p, miR-1273g-3p,miR-6778-5p, miR-328-5p, miR-3679-3p, miR-1228-3p, miR-6779-5p,miR-4723-5p, miR-6850-5p, miR-760, miR-7704, miR-8072, miR-4486,miR-1913, miR-4656, miR-1260b, miR-7106-5p, miR-6889-5p, miR-6780b-5p,miR-6090, miR-4534, miR-4449, miR-5195-3p, miR-1202, miR-4467,miR-6515-3p, miR-4281, miR-4505, miR-4484, miR-6805-3p, miR-3135b,miR-3162-5p, miR-6768-5p, miR-6721-5p, miR-1227-5p, miR-6722-3p,miR-4286, miR-4746-3p, miR-6727-5p, miR-6816-5p, miR-4741, miR-4508,miR-940, miR-4327, miR-4665-3p and miR-718, miR-1203, miR-663b,miR-4258, miR-4649-5p, miR-4516, miR-3619-3p, miR-6826-5p, miR-6757-5p,miR-3131, miR-1343-3p, miR-6775-5p, miR-6813-5p, and miR-3940-5p; andevaluating in vitro whether or not the subject has pancreatic cancersubject using the above-measured expression levels and controlexpression levels of a healthy subject(s) measured in the same way asabove.

As used herein, the term “evaluation” is evaluation support based onresults of in vitro examination, not physician's judgment.

As described above, in the method of the present invention,specifically, miR-6893-5p is hsa-miR-6893-5p, miR-6075 is hsa-miR-6075,miR-6820-5p is hsa-miR-6820-5p, miR-4294 is hsa-miR-4294, miR-6729-5p ishsa-miR-6729-5p, miR-4476 is hsa-miR-4476, miR-6836-3p ishsa-miR-6836-3p, miR-6765-3p is hsa-miR-6765-3p, miR-6799-5p ishsa-miR-6799-5p, miR-4530 is hsa-miR-4530, miR-7641 is hsa-miR-7641,miR-4454 is hsa-miR-4454, miR-615-5p is hsa-miR-615-5p, miR-8073 ishsa-miR-8073, miR-663a is hsa-miR-663a, miR-4634 is hsa-miR-4634,miR-4450 is hsa-miR-4450, miR-4792 is hsa-miR-4792, miR-665 ishsa-miR-665, miR-7975 is hsa-miR-7975, miR-7109-5p is hsa-miR-7109-5p,miR-6789-5p is hsa-miR-6789-5p, miR-4497 is hsa-miR-4497, miR-6877-5p ishsa-miR-6877-5p, miR-6880-5p is hsa-miR-6880-5p, miR-7977 ishsa-miR-7977, miR-4734 is hsa-miR-4734, miR-6821-5p is hsa-miR-6821-5p,miR-8089 is hsa-miR-8089, miR-5585-3p is hsa-miR-5585-3p, miR-6085 ishsa-miR-6085, miR-6845-5p is hsa-miR-6845-5p, miR-4651 is hsa-miR-4651,miR-4433-3p is hsa-miR-4433-3p, miR-1231 is hsa-miR-1231, miR-4665-5p ishsa-miR-4665-5p, miR-7114-5p is hsa-miR-7114-5p, miR-1238-5p ishsa-miR-1238-5p, miR-8069 is hsa-miR-8069, miR-4732-5p ishsa-miR-4732-5p, miR-619-5p is hsa-miR-619-5p, miR-3622a-5p ishsa-miR-3622a-5p, miR-1260a is hsa-miR-1260a, miR-6741-5p ishsa-miR-6741-5p, miR-6781-5p is hsa-miR-6781-5p, miR-6125 ishsa-miR-6125, miR-6805-5p is hsa-miR-6805-5p, miR-6132 is hsa-miR-6132,miR-6872-3p is hsa-miR-6872-3p, miR-6875-5p is hsa-miR-6875-5p,miR-1908-3p is hsa-miR-1908-3p, miR-4433b-3p is hsa-miR-4433b-3p,miR-4736 is hsa-miR-4736, miR-5100 is hsa-miR-5100, miR-6724-5p ishsa-miR-6724-5p, miR-7107-5p is hsa-miR-7107-5p, miR-6726-5p ishsa-miR-6726-5p, miR-3185 is hsa-miR-3185, miR-4638-5p ishsa-miR-4638-5p, miR-1273g-3p is hsa-miR-1273g-3p, miR-6778-5p ishsa-miR-6778-5p, miR-328-5p is hsa-miR-328-5p, miR-3679-3p ishsa-miR-3679-3p, miR-1228-3p is hsa-miR-1228-3p, miR-6779-5p ishsa-miR-6779-5p, miR-4723-5p is hsa-miR-4723-5p, miR-6850-5p ishsa-miR-6850-5p, miR-760 is hsa-miR-760, miR-7704 is hsa-miR-7704,miR-8072 is hsa-miR-8072, miR-4486 is hsa-miR-4486, miR-1913 ishsa-miR-1913, miR-4656 is hsa-miR-4656, miR-1260b is hsa-miR-1260b,miR-7106-5p is hsa-miR-7106-5p, miR-6889-5p is hsa-miR-6889-5p,miR-6780b-5p is hsa-miR-6780b-5p, miR-6090 is hsa-miR-6090, miR-4534 ishsa-miR-4534, miR-4449 is hsa-miR-4449, miR-5195-3p is hsa-miR-5195-3p,miR-1202 is hsa-miR-1202, miR-4467 is hsa-miR-4467, miR-6515-3p ishsa-miR-6515-3p, miR-4281 is hsa-miR-4281, miR-4505 is hsa-miR-4505,miR-4484 is hsa-miR-4484, miR-6805-3p is hsa-miR-6805-3p, miR-3135b ishsa-miR-3135b, miR-3162-5p is hsa-miR-3162-5p, miR-6768-5p ishsa-miR-6768-5p, miR-6721-5p is hsa-miR-6721-5p, miR-1227-5p ishsa-miR-1227-5p, miR-6722-3p is hsa-miR-6722-3p, miR-4286 ishsa-miR-4286, miR-4746-3p is hsa-miR-4746-3p, miR-6727-5p ishsa-miR-6727-5p, miR-6816-5p is hsa-miR-6816-5p, miR-4741 ishsa-miR-4741, miR-4508 is hsa-miR-4508, miR-940 is hsa-miR-940, miR-4327is hsa-miR-4327, miR-4665-3p is hsa-miR-4665-3p, miR-718 is hsa-miR-718,miR-1203 is hsa-miR-1203, miR-663b is hsa-miR-663b, miR-4258 ishsa-miR-4258, miR-4649-5p is hsa-miR-4649-5p, miR-4516 is hsa-miR-4516,miR-3619-3p is hsa-miR-3619-3p, miR-6826-5p is hsa-miR-6826-5p,miR-6757-5p is hsa-miR-6757-5p, miR-3131 is hsa-miR-3131, miR-1343-3p ishsa-miR-1343-3p, miR-6775-5p is hsa-miR-6775-5p, miR-6813-5p ishsa-miR-6813-5p, and miR-3940-5p is hsa-miR-3940-5p.

In the method of the present invention, specifically, the nucleicacid(s) (specifically, probe(s) or primer(s)) is selected from the groupconsisting of the following polynucleotides (a) to (e):

(a) a polynucleotide consisting of a nucleotide sequence represented byany of SEQ ID NOs: 1 to 104, 464 to 473, and 492 to 494 or a nucleotidesequence derived from the nucleotide sequence by the replacement of uwith t, a variant thereof, a derivative thereof, or a fragment thereofcomprising 15 or more consecutive nucleotides;(b) a polynucleotide comprising a nucleotide sequence represented by anyof SEQ ID NOs: 1 to 104, 464 to 473, and 492 to 494;(c) a polynucleotide consisting of a nucleotide sequence complementaryto a nucleotide sequence represented by any of SEQ ID NOs: 1 to 104, 464to 473, and 492 to 494 or a nucleotide sequence derived from thenucleotide sequence by the replacement of u with t, a variant thereof, aderivative thereof, or a fragment thereof comprising 15 or moreconsecutive nucleotides;(d) a polynucleotide comprising a nucleotide sequence complementary to anucleotide sequence represented by any of SEQ ID NOs: 1 to 104, 464 to473, and 492 to 494 or a nucleotide sequence derived from the nucleotidesequence by the replacement of u with t; and(e) a polynucleotide hybridizing under stringent conditions to any ofthe polynucleotides (a) to (d).

The nucleic acid(s) further used in the method of the present inventioncan comprise a nucleic acid(s) capable of specifically binding to atleast one or more polynucleotides selected from the following miRNAs:miR-125a-3p, miR-204-3p, miR-1469, miR-575, miR-150-3p, miR-423-5p,miR-564, miR-3188, miR-1246, miR-602, miR-1290, miR-16-5p, miR-451a,miR-24-3p, miR-187-5p, miR-1908-5p, miR-371a-5p, and miR-550a-5p

Specifically, miR-125a-3p is hsa-miR-125a-3p, miR-204-3p ishsa-miR-204-3p, miR-1469 is hsa-miR-1469, miR-575 is hsa-miR-575,miR-150-3p is hsa-miR-150-3p, miR-423-5p is hsa-miR-423-5p, miR-564 ishsa-miR-564, miR-3188 is hsa-miR-3188, miR-1246 is hsa-miR-1246, miR-602is hsa-miR-602, miR-1290 is hsa-miR-1290, miR-16-5p is hsa-miR-16-5p,miR-451a is hsa-miR-451a, miR-24-3p is hsa-miR-24-3p, miR-187-5p ishsa-miR-187-5p, miR-1908-5p is hsa-miR-1908-5p, miR-371a-5p ishsa-miR-371a-5p, and miR-550a-5p is hsa-miR-550a-5p.

Specifically, the nucleic acid(s) is further selected from the groupconsisting of the following polynucleotides (f) to (j):

(f) a polynucleotide consisting of a nucleotide sequence represented byany of SEQ ID NOs: 105 to 122 or a nucleotide sequence derived from thenucleotide sequence by the replacement of u with t, a variant thereof, aderivative thereof, or a fragment thereof comprising 15 or moreconsecutive nucleotides;(g) a polynucleotide comprising a nucleotide sequence represented by anyof SEQ ID NOs: 105 to 122;(h) a polynucleotide consisting of a nucleotide sequence complementaryto a nucleotide sequence represented by any of SEQ ID NOs: 105 to 122 ora nucleotide sequence derived from the nucleotide sequence by thereplacement of u with t, a variant thereof, a derivative thereof, or afragment thereof comprising 15 or more consecutive nucleotides;(i) a polynucleotide comprising a nucleotide sequence complementary to anucleotide sequence represented by any of SEQ ID NOs: 105 to 122 or anucleotide sequence derived from the nucleotide sequence by thereplacement of u with t; and(j) a polynucleotide hybridizing under stringent conditions to any ofthe polynucleotides (0 to (i).

The nucleic acid(s) further used can comprise a nucleic acid capable ofspecifically binding to at least one or more polynucleotides selectedfrom the following miRNAs: miR-4417, miR-4707-5p, miR-7847-3p, miR-2861,miR-4513, miR-7111-5p, miR-6777-5p, miR-7113-3p, miR-4648, miR-3184-5p,miR-4271, miR-6791-5p, miR-642a-3p, miR-7108-5p, miR-128-1-5p,miR-5196-5p, miR-3178, miR-3656, miR-92a-2-5p, miR-6769b-5p, miR-4689,miR-6076, miR-92b-5p, miR-6774-5p, miR-486-3p, miR-6806-5p, miR-6842-5p,miR-6716-5p, miR-557, miR-4673, miR-4674, miR-4442, miR-1915-3p,miR-4687-3p, and miR-92b-3p.

Specifically, miR-4417 is hsa-miR-4417, miR-4707-5p is hsa-miR-4707-5p,miR-7847-3p is hsa-miR-7847-3p, miR-2861 is hsa-miR-2861, miR-4513 ishsa-miR-4513, miR-7111-5p is hsa-miR-7111-5p, miR-6777-5p ishsa-miR-6777-5p, miR-7113-3p is hsa-miR-7113-3p, miR-4648 ishsa-miR-4648, miR-3184-5p is hsa-miR-3184-5p, miR-4271 is hsa-miR-4271,miR-6791-5p is hsa-miR-6791-5p, miR-642a-3p is hsa-miR-642a-3p,miR-7108-5p is hsa-miR-7108-5p, miR-128-1-5p is hsa-miR-128-1-5p,miR-5196-5p is hsa-miR-5196-5p, miR-3178 is hsa-miR-3178, miR-3656 ishsa-miR-3656, miR-92a-2-5p is hsa-miR-92a-2-5p, miR-6769b-5p ishsa-miR-6769b-5p, miR-4689 is hsa-miR-4689, miR-6076 is hsa-miR-6076,miR-92b-5p is hsa-miR-92b-5p, miR-6774-5p is hsa-miR-6774-5p, miR-486-3pis hsa-miR-486-3p, miR-6806-5p is hsa-miR-6806-5p, miR-6842-5p ishsa-miR-6842-5p, miR-6716-5p is hsa-miR-6716-5p, miR-557 is hsa-miR-557,miR-4673 is hsa-miR-4673, miR-4674 is hsa-miR-4674, miR-4442 ishsa-miR-4442, miR-1915-3p is hsa-miR-1915-3p, miR-4687-3p ishsa-miR-4687-3p, and miR-92b-3p is hsa-miR-92b-3p.

Specifically, the nucleic acid(s) further used is a polynucleotide(s)selected from the group consisting of the following polynucleotides (k)to (o):

(k) a polynucleotide consisting of a nucleotide sequence represented byany of SEQ ID NOs: 349 to 383 or a nucleotide sequence derived from thenucleotide sequence by the replacement of u with t, a variant thereof, aderivative thereof, or a fragment thereof comprising 15 or moreconsecutive nucleotides;(l) a polynucleotide comprising a nucleotide sequence represented by anyof SEQ ID NOs: 349 to 383;(m) a polynucleotide consisting of a nucleotide sequence complementaryto a nucleotide sequence represented by any of SEQ ID NOs: 349 to 383 ora nucleotide sequence derived from the nucleotide sequence by thereplacement of u with t, a variant thereof, a derivative thereof, or afragment thereof comprising 15 or more consecutive nucleotides;(n) a polynucleotide comprising a nucleotide sequence complementary to anucleotide sequence represented by any of SEQ ID NOs: 349 to 383 or anucleotide sequence derived from the nucleotide sequence by thereplacement of u with t; and(o) a polynucleotide hybridizing under stringent conditions to any ofthe polynucleotides (k) to (n).

Examples of the sample used in the method of the present invention caninclude samples prepared from living tissues (preferably pancreatictissues) or body fluids such as blood, serum, plasma, and urine fromsubjects. Specifically, for example, an RNA-containing sample preparedfrom the tissue, a polynucleotide-containing sample further preparedtherefrom, a body fluid such as blood, serum, plasma, or urine, aportion or the whole of a living tissue collected from the subject bybiopsy or the like, or a living tissue excised by surgery can be used,and the sample for measurement can be prepared therefrom.

As used herein, the subject refers to a mammal, for example, a primatesuch as a human or a monkey, a rodent such as a mouse or a rat, a petanimal such as a dog or a cat, and an athletic animal such as a horsewithout any limitation, and is preferably a human.

The steps of the method of the present invention can be changedaccording to the type of the sample to be assayed.

In the case of using RNA as an analyte, the detection of pancreaticcancer (cells) can comprise, for example, the following steps (a), (b),and (c):

(a) a step of binding RNA prepared from a sample from a subject orcomplementary polynucleotides (cDNAs) transcribed from the RNA to apolynucleotide(s) in the kit or the device of the present invention;

(b) a step of measuring the sample-derived RNA or the cDNAs synthesizedfrom the RNA, which is/are bound to the polynucleotide(s), byhybridization using the polynucleotide(s) as a nucleic acid probe(s) orby quantitative RT-PCR using the polynucleotide(s) as a primer(s); and

(c) a step of evaluating the presence or absence of pancreatic cancer(or pancreatic cancer-derived gene expression) on the basis of themeasurement results of the step (b).

For example, various hybridization methods can be used for detecting,examining, evaluating, or diagnosing pancreatic cancer (or pancreaticcancer-derived gene expression) in vitro according to the presentinvention. For example, Northern blot, Southern blot, RT-PCR, DNA chipanalysis, in situ hybridization, Northern hybridization, or Southernhybridization can be used as such a hybridization method.

In the case of using the Northern blot, the presence or absence ofexpression of each gene or the expression level thereof in the RNA canbe detected or measured by use of the nucleic acid probe(s) that can beused in the present invention. Specific examples thereof can include amethod which comprises labeling the nucleic acid probe (or acomplementary strand) with a radioisotope (³²P, ³³P, ³⁵S, etc.), afluorescent material, or the like, hybridizing the labeled product withthe tissue-derived RNA from a subject, which is transferred to a nylonmembrane or the like according to a routine method, and then detectingand measuring a signal derived from the label (radioisotope orfluorescent material) on the formed DNA/RNA duplex using a radiationdetector (examples thereof can include BAS-1800 II (Fujifilm Corp.,Japan)) or a fluorescence detector (examples thereof can include STORM865 (GE Healthcare Japan Corp.)).

In the case of using the quantitative RT-PCR, the presence or absence ofexpression of each gene or the expression level thereof in the RNA canbe detected or measured by use of the primer that can be used in thepresent invention. Specific examples thereof can include a method whichcomprises preparing cDNAs from the tissue-derived RNA of a subjectaccording to a routine method, hybridizing a pair of primers (consistingof a plus strand and a reverse strand binding to the cDNA) prepared fromthe composition for detection of the present invention with the cDNAsuch that the region of each target gene can be amplified with the cDNAas a template, and performing PCR according to a routine method todetect the obtained double-stranded DNA. The method for detecting thedouble-stranded DNA can include a method of performing the PCR using theprimers labeled in advance with a radioisotope or a fluorescentmaterial, a method of electrophoresing the PCR product on an agarose geland staining the double-stranded DNA with ethidium bromide or the likefor detection, and a method of transferring the produced double-strandedDNA to a nylon membrane or the like according to a routine method andhybridizing the double-stranded DNA to a labeled nucleic acid probe fordetection.

In the case of using the nucleic acid array analysis, an RNA chip or aDNA chip in which the composition for detection of the present inventionis attached as nucleic acid probes (single-stranded or double-stranded)to a substrate (solid phase) is used. Regions having the attachednucleic acid probes are referred to as probe spots, and regions havingno attached nucleic acid probe are referred to as blank spots. A groupof genes immobilized on a solid-phase substrate is generally called anucleic acid chip, a nucleic acid array, a microarray, or the like. TheDNA or RNA array includes a DNA or RNA macroarray and a DNA or RNAmicroarray. In the present specification, the term “chip” includes thesearrays. 3D-Gene™ Human miRNA Oligo chip (Toray Industries, Inc.) can beused as the DNA chip, though the DNA chip is not limited thereto.

Examples of the measurement using the DNA chip can include, but are notlimited to, a method of detecting and measuring a signal derived fromthe label on the composition for detection using an image detector(examples thereof can include Typhoon 9410 (GE Healthcare) and 3D-Gene™scanner (Toray Industries, Inc.)).

The “stringent conditions” used herein are, as mentioned above,conditions under which a nucleic acid probe hybridizes to its targetsequence to a detectably larger extent (e.g., a measurement value equalto or larger than “(a mean of background measurement values)+(a standarddeviation of the background measurement values)×2”) than that for othersequences.

The stringent conditions are defined by hybridization and subsequentwashing. Examples of the hybridization conditions include, but notlimited to, 30° C. to 60° C. for 1 to 24 hours in a solution containingSSC, a surfactant, formamide, dextran sulfate, a blocking agent(s), etc.In this context, 1×SSC is an aqueous solution (pH 7.0) containing 150 mMsodium chloride and 15 mM sodium citrate. The surfactant includes, forexample, SDS (sodium dodecyl sulfate), Triton, or Tween. Thehybridization conditions more preferably comprise 3-10×SSC and 0.1-1%SDS. Examples of the conditions for the washing, following thehybridization, which is another condition to define the stringentconditions, can include conditions comprising continuous washing at 30°C. in a solution containing 0.5×SSC and 0.1% SDS, at 30° C. in asolution containing 0.2×SSC and 0.1% SDS, and at 30° C. in a 0.05×SSCsolution. It is desirable that the complementary strand should maintainits hybridized state with a target plus strand even by washing undersuch conditions. Specifically, examples of such a complementary strandcan include a strand consisting of a nucleotide sequence in a completelycomplementary relationship with the nucleotide sequence of the targetplus (+) strand, and a strand consisting of a nucleotide sequence havingat least 80%, preferably at least 85%, more preferably at least 90% orat least 95%, for example, at least 98% or at least 99% identity to thestrand.

Other examples of the “stringent conditions” for the hybridization aredescribed in, for example, Sambrook, J. & Russel, D., Molecular Cloning,A LABORATORY MANUAL, Cold Spring Harbor Laboratory Press, published onJan. 15, 2001, Vol. 1, 7.42 to 7.45 and Vol. 2, 8.9 to 8.17, and can beused in the present invention.

Examples of the conditions for carrying out PCR using polynucleotidefragments in the kit of the present invention as primers includetreatment for approximately 15 seconds to 1 minute at 5 to 10° C. plus aTm value calculated from the sequences of the primers, using a PCRbuffer having composition such as 10 mM Tris-HCL (pH 8.3), 50 mM KCL,and 1 to 2 mM MgCl₂. Examples of the method for calculating such a Tmvalue include Tm value=2×(the number of adenine residues+the number ofthymine residues)+4×(the number of guanine residues+the number ofcytosine residues).

In the case of using the quantitative RT-PCR, a commercially availablekit for measurement specially designed for quantitatively measuringmiRNA, such as TaqMan™ MicroRNA Assays (Life Technologies Corp.),LNA™-based MicroRNA PCR (Exiqon), or Ncode™ miRNA qRT-PCT kit(Invitrogen Corp.) may be used.

For the calculation of gene expression levels, statistical treatmentdescribed in, for example, Statistical analysis of gene expressionmicroarray data (Speed T., Chapman and Hall/CRC), and A beginner's guideMicroarray gene expression data analysis (Causton H. C. et al.,Blackwell publishing) can be used in the present invention, though thecalculation method is not limited thereto. For example, twice,preferably 3 times, more preferably 6 times the standard deviation ofthe measurement values of the blank spots are added to the averagemeasurement value of the blank spots on the DNA chip, and probe spotshaving a signal value equal to or larger than the resulting value can beregarded as detection spots. Alternatively, the average measurementvalue of the blank spots is regarded as a background and can besubtracted from the measurement values of the probe spots to determinegene expression levels. A missing value for a gene expression level canbe excluded from the analyte, preferably replaced with the smallestvalue of the gene expression level in each DNA chip, or more preferablyreplaced with a value obtained by subtracting 0.1 from a logarithmicvalue of the smallest value of the gene expression level. In order toeliminate low-signal genes, only a gene having a gene expression levelof 2⁶, preferably 2⁸, more preferably 2¹⁰ or larger in 20% or more,preferably 50% or more, more preferably 80% or more of the number ofmeasurement samples can be selected as the analyte. Examples of thenormalization of the gene expression level include, but are not limitedto, global normalization and quantile normalization (Bolstad, B. M. etal., 2003, Bioinformatics, Vol. 19, p. 185-193).

The present invention also provides a method comprising measuring targetgenes or gene expression levels in a sample from a subject using thepolynucleotides, the kit, or the device (e.g., chip) for diagnosis ofthe present invention, or a combination thereof, preparing adiscriminant (discriminant function) with gene expression levels in asample from a pancreatic cancer patient and a sample from a healthysubject as supervising samples, and determining or evaluating thepresence and/or absence of the pancreatic cancer-derived genes in thesample.

Specifically, the present invention further provides the methodcomprising: a first step of measuring in vitro expression levels oftarget genes in a plurality of samples known to determine or evaluatethe presence and/or absence of the pancreatic cancer-derived genes inthe samples, using the polynucleotides, the kit, or the device (e.g.,chip) for diagnosis of the present invention, or a combination thereof;a second step of preparing a discriminant with the measurement values ofthe expression levels of the target genes obtained in the first step assupervising samples; a third step of measuring in vitro expressionlevels of the target genes in a sample derived from a subject in thesame way as in the first step; and a fourth step of assigning themeasurement values of the expression levels of the target genes obtainedin the third step to the discriminant obtained in the second step, anddetermining or evaluating the presence and/or absence of the pancreaticcancer-derived genes in the sample on the basis of the results obtainedfrom the discriminant, wherein the target genes can be detected usingthe polynucleotides or using polynucleotides, variants thereof, orfragments thereof contained in the kit or the device (e.g., chip). Inthis context, the discriminant can be prepared by use of Fisher'sdiscriminant analysis, nonlinear discriminant analysis based onMahalanobis' distance, neural network, Support Vector Machine (SVM), orthe like, though the method is not limited thereto.

When a clustering boundary is a straight line or a hyperplane, thelinear discriminant analysis is a method for determining the belongingof a cluster using Formula 1 as a discriminant. In Formula 1, xrepresents an explanatory variable, w represents a coefficient of theexplanatory variable, and w₀ represents a constant term.

$\begin{matrix}{{f(x)} = {w_{0} + {\sum\limits_{i = 1}^{n}{w_{i}x_{i}}}}} & {{Formula}\mspace{14mu} 1}\end{matrix}$

Values obtained from the discriminant are referred to as discriminantscores. The measurement values of a newly offered data set can beassigned as explanatory variables to the discriminant to determineclusters by the signs of the discriminant scores.

The Fisher's discriminant analysis, one type of linear discriminantanalysis, is a dimensionality reduction method for selecting a dimensionsuitable for discriminating classes, and constructs a highlydiscriminating synthetic variable by focusing on the variance of thesynthetic variables and minimizing the variance of data having the samelabel (Venables, W. N. et al., Modern Applied Statistics with S. Fourthedition. Springer, 2002). In the Fisher's discriminant analysis,direction w of projection is determined so as to maximize Formula 2. Inthis formula, μ represents an average input, ng represents the number ofdata belonging to class g, and μg represents an average input of thedata belonging to class g. The numerator and the denominator are theinterclass variance and the intraclass variance, respectively, when eachdata is projected in the direction of the vector w. Discriminantcoefficient w_(i) is determined by maximizing this ratio (TakafumiKanamori et al., “Pattern Recognition”, Kyoritsu Shuppan Co., Ltd.,Tokyo, Japan (2009); and Richard O. et al., Pattern ClassificationSecond Edition., Wiley-Interscience, 2000).

$\begin{matrix}{{{J(w)} = \frac{\sum\limits_{g = 1}^{G}{{n_{g}\left( {{w^{T}\mu_{g}} - {w^{T}\mu}} \right)}\left( {{w^{T}\mu_{g}} - {w^{T}\mu}} \right)^{T}}}{\sum\limits_{g = 1}^{G}{\sum\limits_{{i:y_{i}} = g}^{\;}{\left( {{w^{T}x_{i}} - {w^{T}\mu_{g}}} \right)\left( {{w^{T}x_{i}} - {w^{T}\mu_{g}}} \right)}}}}{{{{subject}\mspace{14mu}{to}\mspace{14mu}\mu} = {\sum\limits_{i = 1}^{n}\frac{x_{i}}{n}}},{\mu_{g} = {\sum\limits_{{i:u_{i}} = g}^{n}\frac{x_{i}}{n_{g}}}}}} & {{Formula}\mspace{14mu} 2}\end{matrix}$

The Mahalanobis' distance is calculated according to Formula 3 inconsideration of data correlation and can be used as nonlineardiscriminant analysis for determining a cluster in which a data pointbelongs to, based on a short Mahalanobis' distance from the data pointto that cluster. In Formula 3, μ represents a central vector of eachcluster, and S⁻¹ represents an inverse matrix of the variance-covariancematrix of the cluster. The central vector is calculated from explanatoryvariable x, and an average vector, a median value vector, or the likecan be used.

$\begin{matrix}{{D\left( {x,\mu} \right)} = \left\{ {\left( {x - \mu} \right)^{t}{S^{- 1}\left( {x - \mu} \right)}} \right\}^{\frac{1}{2}}} & {{Formula}\mspace{14mu} 3}\end{matrix}$

SVM is a discriminant analysis method devised by V. Vapnik (The Natureof Statistical Leaning Theory, Springer, 1995). Particular data pointsof a data set having known classes are defined as explanatory variables,and classes are defined as objective variables. A boundary plane calledhyperplane for correctly classifying the data set into the known classesis determined, and a discriminant for data classification is determinedusing the boundary plane. Then, the measurement values of a newlyoffered data set can be assigned as explanatory variables to thediscriminant to determine classes. In this respect, the result of thediscriminant analysis may be classes, may be a probability of beingclassified into correct classes, or may be the distance from thehyperplane. In SVM, a method of nonlinearly converting a feature vectorto a high dimension and performing linear discriminant analysis in thespace is known as a method for tackling nonlinear problems. Anexpression in which an inner product of two factors in a nonlinearlymapped space is expressed only by inputs in their original spaces iscalled kernel. Examples of the kernel can include a linear kernel, a RBF(Radial Basis Function) kernel, and a Gaussian kernel. While highlydimensional mapping is performed according to the kernel, the optimumdiscriminant, i.e., a discriminant, can be actually constructed by merecalculation according to the kernel, which avoids calculating featuresin the mapped space (e.g., Hideki Aso et al., Frontier of StatisticalScience 6 “Statistics of pattern recognition and learning—New conceptsand approaches”, Iwanami Shoten, Publishers, Tokyo, Japan (2004); NelloCristianini et al., Introduction to SVM, Kyoritsu Shuppan Co., Ltd.,Tokyo, Japan (2008)).

C-support vector classification (C-SVC), one type of SVM, comprisespreparing a hyperplane by supervising a data set with the explanatoryvariables of two groups and classifying an unknown data set into eitherof the groups (C. Cortes et al., 1995, Machine Learning, Vol. 20, p.273-297).

Exemplary calculation of the C-SVC discriminant that can be used in themethod of the present invention will be given below. First, all subjectsare divided into two groups, i.e., a pancreatic cancer patient group anda healthy subject group. For example, pancreatic tissue examination canbe used for a reference under which each subject is confirmed either asa pancreatic cancer patient or as a healthy subject.

Next, a data set consisting of comprehensive gene expression levels ofserum-derived samples of the two divided groups (hereinafter, this dataset is referred to as a training cohort) is prepared, and a C-SVCdiscriminant is determined by using genes found to differ clearly intheir gene expression levels between the two groups as explanatoryvariables and this grouping as objective variables (e.g., −1 and +1). Anoptimizing objective function is represented by Formula 4 wherein erepresents all input vectors, y represents an objective variable, arepresents a Lagrange's undetermined multiplier vector, Q represents apositive definite matrix, and C represents a parameter for adjustingconstrained conditions.

$\begin{matrix}{{{\min\limits_{a}\;{\frac{1}{2}a^{T}{Qa}}} - {e^{T}a}}{{{{subject}\mspace{14mu}{to}\mspace{14mu} y^{T}a} = 0},{0 \leq a_{i} \leq C},{i = 1},\ldots\;,l,}} & {{Formula}\mspace{14mu} 4}\end{matrix}$

Formula 5 is a finally obtained discriminant, and a group in which thedata point belongs to can be determined on the basis of the sign of avalue obtained according to the discriminant. In this formula, xrepresents a support vector, y represents a label indicating thebelonging of a group, a represents the corresponding coefficient, brepresents a constant term, and K represents a kernel function.

$\begin{matrix}{{f(x)} = {{sgn}\left( {{\sum\limits_{i = 1}^{l}{y_{i}a_{i}{K\left( {x_{i},x} \right)}}} + b} \right)}} & {{Formula}\mspace{14mu} 5}\end{matrix}$

For example, a RBF kernel defined by Formula 6 can be used as the kernelfunction. In this formula, x represents a support vector, and yrepresents a kernel parameter for adjusting the complexity of thehyperplane.K(x _(i) , x _(j))=exp(−r∥x _(i)-x _(j)∥²), r<0  Formula 6

In addition, an approach such as neural network, k-nearest neighboralgorithms, decision trees, or logistic regression analysis can beselected as a method for determining or evaluating the presence and/orabsence of expression of a pancreatic cancer-derived target gene(s) in asample derived from a subject, or for evaluating the expression levelthereof by comparison with a control derived from a healthy subject.

The method of the present invention can comprise, for example, thefollowing steps (a), (b), and (c):

(a) a step of measuring an expression level(s) of a target gene(s) intissues containing pancreatic cancer-derived genes derived frompancreatic cancer patients and/or samples already known to be tissuescontaining no pancreatic cancer-derived gene(s) derived from healthysubjects, using the polynucleotide(s), the kit, or the device (e.g., DNAchip) for detection according to the present invention;

(b) a step of preparing the discriminants of Formulas 1 to 3, 5, and 6described above from the measurement values of the expression levelmeasured in the step (a); and

(c) a step of measuring an expression level(s) of the target gene(s) ina sample derived from a subject using the polynucleotide(s), the kit, orthe device (e.g., DNA chip) for diagnosis (detection) according to thepresent invention, assigning the obtained measurement value(s) to thediscriminants prepared in the step (b), and determining or evaluatingthe presence and/or absence of expression of the pancreaticcancer-derived target genes in the sample, or evaluating the expressionlevels thereof by comparison with a healthy subject-derived control, onthe basis of the obtained results.

In this context, in the discriminants of Formulas 1 to 3, 5, and 6, xrepresents an explanatory variable and includes a value obtained bymeasuring a polynucleotide(s) selected from the polynucleotidesdescribed in Section 2 above, or any fragment thereof. Specifically, theexplanatory variable for discriminating a pancreatic cancer patient froma healthy subject according to the present invention is a geneexpression level(s) selected from, for example, the following expressionlevels (1) to (3):

(1) a gene expression level(s) in the serum of a pancreatic cancerpatient or a healthy subject measured by any RNA or DNA comprising 15 ormore consecutive nucleotides in a nucleotide sequence represented by anyof SEQ ID NOs: 1 to 104, 464 to 473, and 492 to 494 or a complementarysequence thereof, or nucleotides derived from the nucleotides by thereplacement of u with t;

(2) a gene expression level(s) in the serum of a pancreatic cancerpatient or a healthy subject measured by any RNA or DNA comprising 15 ormore consecutive nucleotides in a nucleotide sequence represented by anyof SEQ ID NOs: 105 to 122 or a complementary sequence thereof, ornucleotides derived from the nucleotides by the replacement of u with t;and

(3) a gene expression level(s) in the serum of a pancreatic cancerpatient or a healthy subject measured by any RNA or DNA comprising 15 ormore consecutive nucleotides in a nucleotide sequence represented by anyof SEQ ID NOs: 349 to 383 or a complementary sequence thereof, ornucleotides derived from the nucleotides by the replacement of u with t.

As described above, for the method for determining or evaluating thepresence and/or absence of a pancreatic cancer-derived gene(s) in asample derived from a subject, the preparation of a discriminantrequires a discriminant prepared from a training cohort. For enhancingthe accuracy of the discriminant, it is necessary to use genes havingclear difference between two groups in the training cohort whenpreparing the discriminant.

Each gene that is used for an explanatory variable in a discriminant ispreferably determined as follows. First, comprehensive gene expressionlevels of a pancreatic cancer patient group and comprehensive geneexpression levels of a healthy subject group, both of which are in atraining cohort, are used as a data set, the degree of difference in theexpression level of each gene between the two groups is determinedthrough the use of, for example, the P value of t test, which isparametric analysis, or the P value of Mann-Whitney's U test or Wilcoxontest, which is nonparametric analysis.

The gene can be regarded as being statistically significant when thecritical rate (significance level) as the P value obtained by the testis smaller than, for example, 5%, 1%, or 0.01%.

In order to correct an increased probability of type I error attributedto the repetition of a test, a method known in the art, for example,Bonferroni or Holm method, can be used for the correction (e.g., YasushiNagata et al., “Basics of statistical multiple comparison methods”,Scientist Press Co., Ltd. (2007)). As an example of the Bonferronicorrection, for example, the P value obtained by a test is multiplied bythe number of repetitions of the test, i.e., the number of genes used inthe analysis, and the obtained value can be compared with a desiredsignificance level to suppress a probability of causing type I error inthe whole test.

Instead of the test, the absolute value (fold change) of an expressionratio of a median value of each gene expression level between geneexpression levels of a pancreatic cancer patient group and geneexpression levels of a healthy subject group may be calculated to selecta gene that is used for an explanatory variable in a discriminant.Alternatively, ROC curves may be prepared using gene expression levelsof a pancreatic cancer patient group and a healthy subject group, and agene that is used for an explanatory variable in a discriminant can beselected on the basis of an AUROC value.

Next, a discriminant that can be calculated by various methods describedabove is prepared using any number of genes having large difference intheir gene expression levels determined here. Examples of the method forconstructing a discriminant that produces the largest discriminationaccuracy include a method of constructing a discriminant in everycombination of genes that satisfy the significance level being P value,and a method of repetitively evaluating the genes for use in thepreparation of a discriminant while increasing the number of genes oneby one in a descending order of difference in gene expression level(Furey T S. et al., 2000, Bioinformatics., Vol. 16, p. 906-14). A geneexpression level of another independent pancreatic cancer patient orhealthy subject is assigned as an explanatory variable to thisdiscriminant to calculate discrimination results of the group to whichthis independent pancreatic cancer patient or healthy subject belongs.Specifically, the found gene set for diagnosis and the discriminantconstructed using the gene set for diagnosis can be evaluated in anindependent sample cohort to find a more universal gene set fordiagnosis capable of detecting pancreatic cancer and a more universalmethod for discriminating pancreatic cancer.

Split-sample method is preferably used for evaluating the performance(generality) of the discriminant. Specifically, a data set is dividedinto a training cohort and a validation cohort, and gene selection by astatistical test and discriminant preparation are performed using thetraining cohort. Accuracy, sensitivity, and specificity are calculatedusing a result of discriminating a validation cohort according to thediscriminant, and a true group to which the validation cohort belongs,to evaluate the performance of the discriminant. On the other hand,instead of dividing a data set, the gene selection by a statistical testand discriminant preparation may be performed using all of samples, andaccuracy, sensitivity, and specificity can be calculated by thediscriminat anaylsis using a newly prepared sample cohort for evaluationof the performance of the discriminant.

The present invention provides polynucleotides for disease diagnosisuseful in the diagnosis and treatment of pancreatic cancer, a method fordetecting pancreatic cancer using the polynucleotide(s), and a kit and adevice for the detection of pancreatic cancer, comprising thepolynucleotide(s). Particularly, in order to select a gene(s) fordiagnosis and prepare a discriminant so as to exhibit accuracy beyondthe pancreatic cancer diagnosis methods using the existing tumor markersCEA and CA19-9, a gene set for diagnosis and a discriminant for themethod of the present invention can be constructed, which exhibitaccuracy beyond CEA and CA19-9, for example, by comparing expressedgenes in serum from a patient confirmed to be negative using CEA andCA19-9 but finally found to have pancreatic cancer by detailedexamination such as computed tomography using a contrast medium, withgenes expressed in serum from a patient having no pancreatic cancer.

For example, the gene set for diagnosis is set to any combinationselected from one or two or more of the polynucleotides based on anucleotide sequence represented by any of SEQ ID NOs: 1 to 104, 464 to473, and 492 to 494 or a nucleotide sequence derived from the nucleotidesequence by the replacement of u with t, or a complementary sequencethereof as described above; and optionally one or two or more of thepolynucleotides based on a nucleotide sequence represented by any of SEQID NOs: 105 to 122 or a nucleotide sequence derived from the nucleotidesequence by the replacement of u with t, or a complementary sequencethereof; and optionally one or two or more of the polynucleotides basedon a nucleotide sequence represented by any of SEQ ID NOs: 349 to 383 ora nucleotide sequence derived from the nucleotide sequence by thereplacement of u with t, or a complementary sequence thereof. Further, adiscriminant is constructed using expression levels of the gene set fordiagnosis in samples from class I pancreatic cancer patients as a resultof tissue diagnosis and samples from class II healthy subjects as aresult of tissue diagnosis. As a result, the presence or absence ofpancreatic cancer-derived genes in an unknown sample can be determinedwith 100% accuracy at the maximum by measuring expression levels of thegene set for diagnosis in an unknown sample.

EXAMPLES

Hereinafter, the present invention will be described furtherspecifically with reference to Examples below. However, the scope of thepresent invention is not intended to be limited by these Examples.

Reference Example 1

<Collection of samples of pancreatic cancer patient and healthy subject>

Sera were collected using VENOJECT II vacuum blood collecting tubeVP-AS109K60 (Terumo Corp., Japan) from 100 healthy subjects and 67pancreatic cancer patients (1 case with stage IB, 10 cases with stageIIB, 17 cases with stage III, and 39 cases with stage IV) confirmed tohave no cancer in organs other than the pancreas after obtainment ofinformed consent, and used as a training cohort. Likewise, sera werecollected using VENOJECT II vacuum blood collecting tube VP-AS109K60(Terumo Corp.) from 50 healthy subjects and 33 pancreatic cancerpatients (1 case with stage IB, 2 cases with stage IIA, 4 cases withstage IIB, 11 cases with stage III, and 15 cases with stage IV)confirmed to have no cancer in organs other than the pancreas afterobtainment of informed consent, and used as a validation cohort.

<Extraction of Total RNA>

Total RNA was obtained using a reagent for RNA extraction in 3D-Gene™RNA extraction reagent from liquid sample kit (Toray Industries, Inc.,Japan) according to the protocol provided by the manufacturer from 300μL of the serum sample obtained from each of 250 persons in total of 150healthy subjects and 100 pancreatic cancer patients included in thetraining cohort and the validation cohort.

<Measurement of Gene Expression Level>

miRNAs in the total RNA obtained from the serum samples of each of 250persons in total of 150 healthy subjects and 100 pancreatic cancerpatients included in the training cohort and the validation cohort werefluorescently labeled using 3D-Gene™ miRNA Labeling kit (TorayIndustries, Inc.) according to the protocol (ver 2.20) provided by themanufacturer. The oligo DNA chip used was 3D-Gene™ Human miRNA Oligochip (Toray Industries, Inc.) with attached probes having sequencescomplementary to 2,555 miRNAs among the miRNAs registered in miRBaseRelease 20. Hybridization under stringent conditions and washingfollowing the hybridization were performed according to the protocolprovided by the manufacturer. The DNA chip was scanned using 3D-Gene™scanner (Toray Industries, Inc.) to obtain images. Fluorescenceintensity was digitized using 3D-Gene™ Extraction (Toray Industries,Inc.). The digitized fluorescence intensity was converted to alogarithmic value having a base of 2 and used as a gene expressionlevel, from which a blank value was subtracted. A missing value wasreplaced with a value obtained by subtracting 0.1 from a logarithmicvalue of the smallest value of the gene expression level in each DNAchip. As a result, the comprehensive gene expression levels of themiRNAs in the sera were obtained for the 100 pancreatic cancer patientsand the 150 healthy subjects. Calculation and statistical analysis usingthe digitized gene expression levels of the miRNAs were carried outusing R language 3.0.2 (R Development Core Team (2013). R: A languageand environment for statistical computing. R Foundation for StatisticalComputing, URL http://www.R-project.org/.) and MASS package 7.3-30(Venables, W. N. & Ripley, B. D. (2002) Modern Applied Statistics withS. Fourth Edition. Springer, New York. ISBN 0-387-95457-0).

Reference Example 2

<Collection of Samples of Other Cancers and Benign Diseases>

Sera were collected using VENOJECT II vacuum blood collecting tubeVP-AS109K60 (Terumo Corp.) from each of 35 colorectal cancer patients,37 stomach cancer patients, 32 esophageal cancer patients, 38 livercancer patients, and 13 benign pancreaticobiliary disease patientsconfirmed to have no cancer in other organs after obtainment of informedconsent, and used as a training cohort together with the samples of 67pancreatic cancer patients (1 case with stage IIA, 11 cases with stageIIB, 17 cases with stage III, and 38 cases with stage IV) and 93 healthysubjects of Reference Example 1. Likewise, sera were collected usingVENOJECT II vacuum blood collecting tube VP-AS109K60 (Terumo Corp.) fromeach of 15 colorectal cancer patients, 13 stomach cancer patients, 18esophageal cancer patients, 12 liver cancer patients, and 8 benignpancreaticobiliary disease patients confirmed to have no cancer in otherorgans after obtainment of informed consent, and used as a validationcohort together with the samples of 33 pancreatic cancer patients (2cases with stage IB, 1 case with stage IIA, 3 cases with stage IIB, 11cases with stage III, and 16 cases with stage IV) and 57 healthysubjects of Reference Example 1. Subsequent extraction of total RNA andmeasurement and analysis of gene expression levels were conducted in thesame way as in Reference Example 1.

Example 1

<Selection of Gene Markers Using the Training Cohort, and Method forEvaluating Pancreatic Cancer Discriminant Performance of the Single GeneMarker Using the Validation Cohort>

In this Example, a gene marker for discriminating a pancreatic cancerpatient from a healthy subject was selected from the training cohort andstudied in the validation cohort independent of the training cohort.

Specifically, first, the miRNA expression levels of the training cohortand the validation cohort obtained in the preceding Reference Exampleswere combined and normalized by quantile normalization.

Next, genes for diagnosis were selected using the training cohort. Here,in order to acquire diagnostic markers with higher reliability, onlygenes having the expression level of 2⁶ or higher in 50% or more of thesamples in either of the pancreatic cancer patient group of the trainingcohort or the healthy subject group of the training cohort wereselected. In order to further acquire statistically significant genesfor discriminating a pancreatic cancer patient group from a healthysubject group, the P value obtained by two-tailed t-test assuming equalvariance as to each gene expression level was corrected by theBonferroni method, and genes that satisfied p<0.01 were acquired as genemarkers for use in explanatory variables of a discriminant and describedin Table 2.

In this way, hsa-miR-6893-5p, hsa-miR-6075, hsa-miR-6820-5p,hsa-miR-4294, hsa-miR-6729-5p, hsa-miR-4476, hsa-miR-6836-3p,hsa-miR-6765-3p, hsa-miR-6799-5p, hsa-miR-4530, hsa-miR-7641,hsa-miR-4454, hsa-miR-615-5p, hsa-miR-8073, hsa-miR-663a, hsa-miR-4634,hsa-miR-4450, hsa-miR-4792, hsa-miR-665, hsa-miR-7975, hsa-miR-7109-5p,hsa-miR-6789-5p, hsa-miR-4497, hsa-miR-6877-5p, hsa-miR-6880-5p,hsa-miR-7977, hsa-miR-4734, hsa-miR-6821-5p, hsa-miR-8089,hsa-miR-5585-3p, hsa-miR-6085, hsa-miR-6845-5p, hsa-miR-4651,hsa-miR-4433-3p, hsa-miR-1231, hsa-miR-4665-5p, hsa-miR-7114-5p,hsa-miR-1238-5p, hsa-miR-8069, hsa-miR-4732-5p, hsa-miR-619-5p,hsa-miR-3622a-5p, hsa-miR-1260a, hsa-miR-6741-5p, hsa-miR-6781-5p,hsa-miR-6125, hsa-miR-6805-5p, hsa-miR-6132, hsa-miR-6872-3p,hsa-miR-6875-5p, hsa-miR-1908-3p, hsa-miR-4433b-3p, hsa-miR-4736,hsa-miR-5100, hsa-miR-6724-5p, hsa-miR-7107-5p, hsa-miR-6726-5p,hsa-miR-3185, hsa-miR-4638-5p, hsa-miR-1273g-3p, hsa-miR-6778-5p,hsa-miR-328-5p, hsa-miR-3679-3p, hsa-miR-1228-3p, hsa-miR-6779-5p,hsa-miR-4723-5p, hsa-miR-6850-5p, hsa-miR-760, hsa-miR-7704,hsa-miR-8072, hsa-miR-4486, hsa-miR-1913, hsa-miR-4656, hsa-miR-1260b,hsa-miR-7106-5p, hsa-miR-6889-5p, hsa-miR-6780b-5p, hsa-miR-6090,hsa-miR-4534, hsa-miR-4449, hsa-miR-5195-3p, hsa-miR-1202, hsa-miR-4467,hsa-miR-6515-3p, hsa-miR-4281, hsa-miR-4505, hsa-miR-4484,hsa-miR-6805-3p, hsa-miR-3135b, hsa-miR-3162-5p, hsa-miR-6768-5p,hsa-miR-6721-5p, hsa-miR-1227-5p, hsa-miR-6722-3p, hsa-miR-4286,hsa-miR-4746-3p, hsa-miR-6727-5p, hsa-miR-6816-5p, hsa-miR-4741,hsa-miR-4508, hsa-miR-940, hsa-miR-4327, hsa-miR-4665-3p, hsa-miR-718,hsa-miR-125a-3p, hsa-miR-204-3p, hsa-miR-1469, hsa-miR-575,hsa-miR-150-3p, hsa-miR-423-5p, hsa-miR-564, hsa-miR-3188, hsa-miR-1246,hsa-miR-602, hsa-miR-1290, hsa-miR-16-5p, hsa-miR-451a, hsa-miR-24-3p,hsa-miR-187-5p, hsa-miR-1908-5p, hsa-miR-371a-5p, and hsa-miR-550a-5pgenes, and the nucleotide sequences of SEQ ID NOs: 1 to 122 relatedthereto were found.

A discriminant for determining the presence or absence of pancreaticcancer was further prepared by Fisher's discriminant analysis with theexpression levels of these genes as indicators. Specifically, any newlyfound polynucleotide consisting of a nucleotide sequence represented byany of SEQ ID NOs: 1 to 104 among the 122 genes selected in the trainingcohort was input to Formula 2 above to prepare a discriminant.Calculated accuracy, sensitivity, and specificity are shown in Table 3.In this respect, a discriminant coefficient and a constant term areshown in Table 4.

Next, accuracy, sensitivity, and specificity in the validation cohortwere calculated using the discriminant thus prepared, and thediscriminant performance of the selected polynucleotides was validatedusing independent samples (Table 3). For example, the expression levelmeasurement value of the nucleotide sequence represented by SEQ ID NO: 1was compared between the healthy subjects (50 persons) and thepancreatic cancer patients (33 persons) in the validation cohort. As aresult, the gene expression level measurement values in the trainingcohort were found to be significantly lower in the pancreatic cancerpatient group than in the healthy subject group (see the left diagram ofFIG. 2). These results were also reproducible in the validation cohort(see the right diagram of FIG. 2). Likewise, the results obtained aboutthe other polynucleotides shown in SEQ ID NOs: 1 to 122 showed that thegene expression level measurement values were significantly lower (−) orhigher (+) in the pancreatic cancer patient group than in the healthysubject group (Table 2). These results were able to be validated in thevalidation cohort. For example, as for this nucleotide sequencerepresented by SEQ ID NO: 1, the number of correctly or incorrectlyidentified samples in the detection of pancreatic cancer was calculatedusing the threshold (8.02) that was set in the training cohort anddiscriminated between the two groups. As a result, 30 true positives, 49true negatives, 1 false positive, and 3 false negatives were obtained.From these values, 95% accuracy, 91% sensitivity, and 98% specificitywere obtained as the detection performance. In this way, the detectionperformance was calculated as to all of the polynucleotides shown in SEQID NOs: 1 to 122, and described in Table 3. Among the polynucleotidesconsisting of the nucleotide sequences represented by SEQ ID NOs: 1 to104 shown in Table 2, for example, 14 polynucleotides consisting of thenucleotide sequences represented by SEQ ID NOs: 1, 2, 4, 5, 7, 9, 11,18, 21, 22, 24, 25, 35, and 46 exhibited sensitivity of 87.9%, 90.9%,87.9%, 81.8%, 90.9%, 78.8%, 78.8%, 78.8%, 84.8%, 78.8%, 81.8%, 81.8%,93.9%, and 81.8%, respectively, in the validation cohort (Table 3).Also, these polynucleotides were able to correctly identify one stage 1pancreatic cancer sample contained in the validation cohort as apancreatic cancer sample. Furthermore, these polynucleotides were ableto correctly discriminate pancreatic cancer as to any of the tumorsoccupying the head, the body, and the tail of the pancreas in thevalidation cohort, and, particularly, were able to detect tumors even inthe tail of the pancreas, which are prone to delayed diagnosis. As seenfrom Comparative Example mentioned later, the existing markers CEA andCA19-9 had sensitivity of 45.5% and 75.8%, respectively, in thevalidation cohort (Table 5), demonstrating that, for example, the 14polynucleotides consisting of the nucleotide sequences represented bySEQ ID Nos: 1, 2, 4, 5, 7, 9, 11, 18, 21, 22, 24, 25, 35, and 46 candiscriminate, each alone, pancreatic cancer in the validation cohortwith sensitivity beyond CA19-9.

Example 2

<Method a for Evaluating Pancreatic Cancer Discriminant Performance byCombination of Plurality of Gene Markers Using Samples in the ValidationCohort>

In this Example, a method for evaluating pancreatic cancer discriminantperformance by a combination of the gene markers selected in Example 1was studied.

Specifically, Fisher's discriminant analysis was conducted as to 7,228combinations of two expression level measurement values comprising atleast one or more of the expression level measurement values of thenewly found polynucleotides consisting of the nucleotide sequencesrepresented by SEQ ID NOs: 1 to 104 among the polynucleotides consistingof the nucleotide sequences represented by SEQ ID NOs: 1 to 122 selectedin Example 1, to construct a discriminant for determining the presenceor absence of pancreatic cancer. Next, accuracy, sensitivity, andspecificity in the validation cohort were calculated using thediscriminant thus prepared, and the discriminant performance of theselected polynucleotides was validated using independent samples. Forexample, the expression level measurement values of the nucleotidesequences represented by SEQ ID NO: 1 and SEQ ID NO: 2 were comparedbetween the healthy subjects (50 persons) and the pancreatic cancerpatients (33 persons) in the validation cohort. As a result, a scatterdiagram that significantly separated the expression level measurementvalues of the pancreatic cancer patient group from those of the healthysubject group was obtained in the training cohort (see the left diagramof FIG. 3). These results were also reproducible in the validationcohort (see the right diagram of FIG. 3). Likewise, a scatter diagramthat significantly separated the gene expression level measurementvalues of the pancreatic cancer patient group from those of the healthysubject group was also obtained as to the other combinations of twoexpression level measurement values comprising at least one or more ofthe expression level measurement values of the newly foundpolynucleotides consisting of the nucleotide sequences represented bySEQ ID NOs: 1 to 104 among the polynucleotides consisting of thenucleotide sequences represented by SEQ ID NOs: 1 to 122. These resultswere able to be validated in the validation cohort. For example, as forthese nucleotide sequences represented by SEQ ID NO: 1 and SEQ ID NO: 2,the number of samples that were correctly or incorrectly identifiedpancreatic cancer was calculated using the threshold (0=1.74x+y+5.14)that was set in the training cohort and discriminated between the twogroups. As a result, 30 true positives, 49 true negatives, 1 falsepositive, and 3 false negatives were obtained. From these values, 95%accuracy, 91% sensitivity, and 98% specificity were obtained as thedetection performance. In this way, the detection performance wascalculated for the combinations of two expression level measurementvalues comprising at least one or more of the expression levelmeasurement values of the newly found polynucleotides consisting of thenucleotide sequences represented by SEQ ID NOs: 1 to 104 among thepolynucleotides consisting of the nucleotide sequences represented bySEQ ID NOs: 1 to 122, and the 2,619 combinations that showed sensitivitybetter than the sensitivity (75.8%) of the existing marker in thevalidation cohort, were described in Table 6.

The discriminant analysis for pancreatic cancer in the validation cohortwas performed using the 7,228 combinations of the expression levelmeasurement values of the polynucleotides. As a result, for example, thecombinations of the expression level measurement values of thepolynucleotides consisting of the nucleotide sequences represented bySEQ ID NOs: 2 and 105, SEQ ID NOs: 18 and 105, SEQ ID NOs: 46 and 105,and SEQ ID NOs: 55 and 105 exhibited sensitivity of 100%, 100%, and100%, respectively, in the validation cohort. In this way, the 2,691combinations of the expression level measurement values of thepolynucleotides having sensitivity beyond the existing marker CA19-9(Table 5) were obtained in the validation cohort. All of the nucleotidesequences 1 to 122 described in Table 2 obtained in Example 1 wereemployed at least once in these combinations. These results demonstratedthat the combinations of two expression level measurement valuescomprising at least one or more of the expression level measurementvalues of the polynucleotides consisting of the nucleotide sequencesrepresented by SEQ ID NOs: 1 to 122 can detect pancreatic cancer withsensitivity beyond CA19-9 in the validation cohort.

Thus, markers capable of detecting pancreatic cancer with excellentsensitivity are obtained even if 3, 4, 5, 6, 7, 8, 9, 10 or more of theexpression level measurement values of the polynucleotides consisting ofthe nucleotide sequences represented by SEQ ID NOs: 1 to 122 arecombined. For example, the polynucleotides consisting of the nucleotidesequences represented by SEQ ID NOs: 1 to 122 selected in Example 1 wereranked in the descending order of their P values which indicatestatistical significance, and detection performance was calculated usingcombinations of one or more miRNAs to which the miRNAs were added one byone from the top to the bottom according to the rank. As a result, thesensitivity in the validation cohort was 87.9% for 2 miRNAs, 90.9% for 3miRNAs, 100% for 5 miRNAs, 100% for 10 miRNAs, 100% for 20 miRNAs, 100%for 50 miRNAs, 100% for 100 miRNAs, and 100% for 122 miRNAs. Thesevalues of the sensitivity were higher than the sensitivity of theexisting tumor marker in blood, demonstrating that even combinations ofa plurality of the miRNAs can serve as excellent markers for thedetection of pancreatic cancer. In this context, the combinations of aplurality of the miRNAs are not limited to the combinations of themiRNAs added in the order of statistically significant difference asdescribed above, and any combination of a plurality of the miRNAs can beused in the detection of pancreatic cancer.

From these results, it can be concluded that all of the polynucleotidesconsisting of the nucleotide sequences represented by SEQ ID NOs: 1 to122 serve as excellent diagnosticmarkers.

Tables 2, 3, 4, 5, and 6 mentioned above are as follows.

TABLE 2 Expression level in P value after pancreatic cancer Bonferronipatient relative to SEQ ID NO: Gene name correction healthy subject 1hsa-miR-6893-5p 7.19E−46 − 2 hsa-miR-6075 1.91E−29 + 3 hsa-miR-6820-5p1.78E−27 − 4 hsa-miR-4294 3.27E−27 − 5 hsa-miR-6729-5p 6.76E−26 + 6hsa-miR-4476 8.49E−25 − 7 hsa-miR-6836-3p 1.97E−22 + 8 hsa-miR-6765-3p4.75E−22 − 9 hsa-miR-6799-5p 5.00E−19 − 10 hsa-miR-4530 9.09E−19 − 11hsa-miR-7641 7.84E−18 − 12 hsa-miR-4454 1.29E−17 − 13 hsa-miR-615-5p3.14E−17 − 14 hsa-miR-8073 3.61E−17 + 15 hsa-miR-663a 1.72E−16 + 16hsa-miR-4634 2.55E−16 + 17 hsa-miR-4450 3.14E−16 − 18 hsa-miR-47923.80E−16 + 19 hsa-miR-665 7.86E−16 + 20 hsa-miR-7975 8.48E−15 − 21hsa-miR-7109-5p 3.23E−14 − 22 hsa-miR-6789-5p 4.58E−13 + 23 hsa-miR-44975.38E−13 − 24 hsa-miR-6877-5p 5.58E−13 − 25 hsa-miR-6880-5p 6.14E−13 −26 hsa-miR-7977 6.28E−13 − 27 hsa-miR-4734 6.79E−13 + 28 hsa-miR-6821-5p8.22E−13 − 29 hsa-miR-8089 9.61E−13 − 30 hsa-miR-5585-3p 1.38E−12 + 31hsa-miR-6085 4.32E−12 − 32 hsa-miR-6845-5p 1.41E−11 + 33 hsa-miR-46511.53E−11 − 34 hsa-miR-4433-3p 5.65E−11 + 35 hsa-miR-1231 1.38E−10 + 36hsa-miR-4665-5p 2.54E−10 − 37 hsa-miR-7114-5p 5.73E−10 − 38hsa-miR-1238-5p 6.26E−10 + 39 hsa-miR-8069 7.39E−10 + 40 hsa-miR-4732-5p8.03E−10 + 41 hsa-miR-619-5p 2.23E−09 + 42 hsa-miR-3622a-5p 2.53E−09 −43 hsa-miR-1260a 3.84E−09 − 44 hsa-miR-6741-5p 6.57E−09 − 45hsa-miR-6781-5p 6.86E−09 + 46 hsa-miR-6125 7.51E−09 + 47 hsa-miR-6805-5p8.71E−09 + 48 hsa-miR-6132 1.71E−08 − 49 hsa-miR-6872-3p 1.74E−08 − 50hsa-miR-6875-5p 2.76E−08 + 51 hsa-miR-1908-3p 2.77E−08 + 52hsa-miR-4433b-3p 5.12E−08 + 53 hsa-miR-4736 5.45E−08 + 54 hsa-miR-51007.94E−08 − 55 hsa-miR-6724-5p 9.14E−08 + 56 hsa-miR-7107-5p 9.80E−08 −57 hsa-miR-6726-5p 2.49E−07 − 58 hsa-miR-3185 2.57E−07 + 59hsa-miR-4638-5p 6.78E−07 − 60 hsa-miR-1273g-3p 6.87E−07 + 61hsa-miR-6778-5p 6.95E−07 + 62 hsa-miR-328-5p 7.01E−07 − 63hsa-miR-3679-3p 7.68E−07 + 64 hsa-miR-1228-3p 9.27E−07 + 65hsa-miR-6779-5p 1.28E−06 − 66 hsa-miR-4723-5p 1.35E−06 − 67hsa-miR-6850-5p 1.68E−06 + 68 hsa-miR-760 1.69E−06 − 69 hsa-miR-77041.82E−06 − 70 hsa-miR-8072 5.28E−06 + 71 hsa-miR-4486 8.48E−06 + 72hsa-miR-1913 1.02E−05 + 73 hsa-miR-4656 1.36E−05 + 74 hsa-miR-1260b3.21E−05 − 75 hsa-miR-7106-5p 3.55E−05 − 76 hsa-miR-6889-5p 4.00E−05 −77 hsa-miR-6780b-5p 4.32E−05 + 78 hsa-miR-6090 5.02E−05 + 79hsa-miR-4534 1.36E−04 − 80 hsa-miR-4449 1.63E−04 + 81 hsa-miR-5195-3p1.70E−04 − 82 hsa-miR-1202 1.83E−04 − 83 hsa-miR-4467 7.51E−04 + 84hsa-miR-6515-3p 8.23E−04 + 85 hsa-miR-4281 8.83E−04 − 86 hsa-miR-45058.88E−04 − 87 hsa-miR-4484 9.98E−04 + 88 hsa-miR-6805-3p 1.04E−03 + 89hsa-miR-3135b 1.11E−03 − 90 hsa-miR-3162-5p 1.26E−03 − 91hsa-miR-6768-5p 1.45E−03 − 92 hsa-miR-6721-5p 1.57E−03 + 93hsa-miR-1227-5p 1.65E−03 + 94 hsa-miR-6722-3p 1.66E−03 + 95 hsa-miR-42861.73E−03 − 96 hsa-miR-4746-3p 1.83E−03 + 97 hsa-miR-6727-5p 3.32E−03 −98 hsa-miR-6816-5p 4.09E−03 + 99 hsa-miR-4741 4.57E−03 + 100hsa-miR-4508 6.50E−03 + 101 hsa-miR-940 7.02E−03 − 102 hsa-miR-43277.54E−03 − 103 hsa-miR-4665-3p 7.88E−03 + 104 hsa-miR-718 9.73E−03 + 105hsa-miR-125a-3p 2.01E−50 − 106 hsa-miR-204-3p 1.58E−30 − 107hsa-miR-1469 1.67E−28 + 108 hsa-miR-575 1.50E−26 − 109 hsa-miR-150-3p7.09E−23 − 110 hsa-miR-423-5p 4.74E−21 − 111 hsa-miR-564 2.56E−10 − 112hsa-miR-3188 2.93E−09 + 113 hsa-miR-1246 3.33E−08 + 114 hsa-miR-6021.67E−06 + 115 hsa-miR-1290 3.00E−06 + 116 hsa-miR-16-5p 3.74E−06 − 117hsa-miR-451a 1.28E−05 − 118 hsa-miR-24-3p 4.71E−05 − 119 hsa-miR-187-5p1.11E−04 − 120 hsa-miR-1908-5p 4.29E−04 + 121 hsa-miR-371a-5p 1.56E−03 −122 hsa-miR-550a-5p 8.60E−03 +

TABLE 3 Training cohort Validation cohort Accuracy SensitivitySpecificity Accuracy Sensitivity Specificity SEQ ID NO: (%) (%) (%) (%)(%) (%) 1 95.8 94 97 92.8 87.9 96 2 88.6 74.6 98 96.4 90.9 100 3 90.485.1 94 78.3 66.7 86 4 86.8 74.6 95 88 87.9 88 5 88 85.1 90 84.3 81.8 866 86.2 73.1 95 81.9 69.7 90 7 91.6 86.6 95 92.8 90.9 94 8 85 73.1 9384.3 69.7 94 9 85 80.6 88 83.1 78.8 86 10 83.2 77.6 87 79.5 75.8 82 1179 68.7 86 81.9 78.8 84 12 81.9 71.2 89 80.7 66.7 90 13 82 77.6 85 81.972.7 88 14 82 65.7 93 78.3 54.5 94 15 83.2 64.2 96 85.5 66.7 98 16 80.873.1 86 74.7 63.6 82 17 83.8 65.7 96 81.9 72.7 88 18 85 77.6 90 89.278.8 96 19 79.6 64.2 90 81.9 63.6 94 20 75.4 64.2 83 73.5 51.5 88 2176.6 70.1 81 81.9 84.8 80 22 77.8 62.7 88 83.1 78.8 86 23 75.4 58.2 8765.9 46.9 78 24 76 59.7 87 83.1 81.8 84 25 80.8 67.2 90 86.7 81.8 90 2676.6 61.2 87 73.5 48.5 90 27 77.2 62.7 87 75.9 51.5 92 28 76 65.7 8371.1 69.7 72 29 76 62.7 85 74.7 63.6 82 30 79.6 68.7 87 83.1 63.6 96 3176 62.7 85 74.7 72.7 76 32 79 64.2 89 71.1 48.5 86 33 78.4 58.2 92 80.760.6 94 34 79 74.6 82 75.9 66.7 82 35 77.8 61.2 89 88 93.9 84 36 76 59.787 69.9 51.5 82 37 74.9 61.2 84 79.5 63.6 90 38 77.8 52.2 95 78.3 51.596 39 74.9 52.2 90 83.1 66.7 94 40 79.6 56.7 95 75.9 54.5 90 41 76 56.789 75.9 45.5 96 42 78.4 53.7 95 78.3 66.7 86 43 75.4 61.2 85 68.7 36.490 44 77.8 61.2 89 75.9 57.6 88 45 71.9 59.7 80 69.9 54.5 80 46 75.462.7 84 84.3 81.8 86 47 71.3 50.7 85 68.7 45.5 84 48 75.4 56.7 88 73.548.5 90 49 72.5 53.7 85 66.3 39.4 84 50 68.9 49.3 82 75.6 68.8 80 5177.2 62.7 87 78.3 66.7 86 52 78.4 70.1 84 72.3 63.6 78 53 74.9 55.2 8873.5 51.5 88 54 74.9 53.7 89 72.3 51.5 86 55 73.7 56.7 85 74.7 63.6 8256 72.5 56.7 83 67.5 54.5 76 57 74.9 47.8 93 78.3 54.5 94 58 75.4 56.788 81.9 72.7 88 59 75.4 55.2 89 75.9 57.6 88 60 74.3 46.3 93 71.1 39.492 61 74.3 52.2 89 72.3 42.4 92 62 71.3 64.2 76 69.9 57.6 78 63 67.147.8 80 61.4 42.4 74 64 74.3 59.7 84 74.7 66.7 80 65 71.9 55.2 83 79.566.7 88 66 77.8 64.2 87 81.9 75.8 86 67 70.1 47.8 85 75.9 69.7 80 6869.5 46.3 85 68.7 45.5 84 69 74.9 62.7 83 63.9 54.5 70 70 77.2 59.7 8971.1 60.6 78 71 70.7 46.3 87 72.3 42.4 92 72 70.7 50.7 84 65.9 39.4 83.773 72.5 47.8 89 69.9 33.3 94 74 71.3 44.8 89 71.1 45.5 88 75 71.9 50.786 78.3 69.7 84 76 65.3 37.3 84 65.1 30.3 88 77 71.9 50.7 86 75.3 58.186 78 68.3 56.7 76 68.7 66.7 70 79 74.9 53.7 89 79.5 69.7 86 80 70.143.3 88 75.9 54.5 90 81 71.7 51.5 85 75.9 57.6 88 82 65.3 40.3 82 74.760.6 84 83 65.9 38.8 84 77.1 63.6 86 84 66.5 43.3 82 60.2 36.4 76 8566.5 46.3 80 74.7 45.5 94 86 71.9 44.8 90 67.5 36.4 88 87 64.7 41.8 8065.1 36.4 84 88 64.7 40.3 81 67.5 45.5 82 89 71.9 47.8 88 77.1 57.6 9090 70.7 41.8 90 72.3 45.5 90 91 70.7 43.3 89 69.9 42.4 88 92 68.9 50.781 68.7 57.6 76 93 62.9 38.8 79 69.9 51.5 82 94 68.3 35.8 90 78.3 63.688 95 66.5 41.8 83 60.2 27.3 82 96 70.1 44.8 87 79.5 60.6 78 97 73.749.3 90 69.9 45.5 84 98 75.3 57.6 87 77.1 60.6 86 99 67.7 43.3 84 73.554.5 82 100 64.1 28.4 88 63.9 39.4 90 101 62.9 31.3 84 62.7 27.3 94 10268.9 43.3 86 66.3 24.2 84 103 72.5 46.3 90 74.7 63.6 82 104 70.1 44.8 8768.7 45.5 86

TABLE 4 SEQ ID NO: Discriminant coefficient Constant term 1 2.460 19.7142 2.382 21.068 3 3.095 21.899 4 2.352 23.243 5 7.904 99.660 6 1.4279.523 7 2.999 26.661 8 1.567 13.180 9 4.320 34.683 10 2.347 21.497 111.240 8.775 12 2.099 24.008 13 2.507 16.240 14 2.542 16.656 15 3.00330.919 16 5.690 56.064 17 1.236 6.777 18 1.762 12.038 19 2.603 19.023 201.993 19.451 21 5.292 39.055 22 4.377 43.459 23 2.108 26.455 24 3.95728.165 25 2.128 15.182 26 1.961 18.889 27 4.907 58.675 28 4.501 38.36229 3.320 21.613 30 1.615 9.456 31 5.158 53.443 32 3.419 32.836 33 4.11244.623 34 3.556 26.261 35 3.089 20.506 36 2.763 26.001 37 4.150 28.31238 2.643 17.528 39 5.818 74.782 40 1.432 9.710 41 1.548 12.083 42 3.01617.886 43 2.295 15.780 44 3.562 24.535 45 4.999 52.068 46 4.621 55.32247 5.752 65.582 48 3.690 28.014 49 2.300 13.896 50 3.446 30.899 51 2.75419.334 52 3.342 26.922 53 2.877 17.377 54 2.361 24.174 55 3.775 37.57756 4.572 35.653 57 2.278 22.355 58 1.996 14.097 59 1.651 10.003 60 2.12016.586 61 2.027 16.365 62 4.550 49.932 63 3.688 22.416 64 4.384 27.79165 5.587 39.777 66 2.642 23.269 67 4.993 56.756 68 2.773 24.275 69 6.97396.404 70 4.314 53.140 71 2.482 17.866 72 3.669 22.882 73 3.449 25.51774 2.141 18.183 75 2.787 16.795 76 2.574 18.040 77 3.025 26.735 78 6.73687.662 79 2.855 19.214 80 3.280 21.398 81 3.072 21.250 82 3.225 21.27283 1.954 19.003 84 4.310 29.038 85 3.905 45.270 86 4.055 33.489 87 2.76731.507 88 2.531 18.803 89 2.479 19.469 90 2.939 21.665 91 3.025 28.50992 3.753 28.267 93 6.207 58.913 94 5.548 47.238 95 2.358 17.589 96 2.48716.190 97 5.449 69.434 98 3.843 38.475 99 3.266 32.112 100 6.751 87.358101 3.318 20.579 102 4.434 37.869 103 3.950 23.214 104 3.491 23.806

TABLE 5-1 Training cohort Sample name Cancer stage CEA (ng/mL) CA19-9(U/mL) P01 III 5.6 (+) 202.7 (+) P05 IV 7.9 (+) 2535 (+) P06 IV 5.7 (+)2381 (+) P07 IB 0.7 (−) 81.9 (+) P09 IV 1 (−) 48.6 (+) P10 IIB 3.3 (−)85.4 (+) P11 IV 1.4 (−) 8.4 (−) P12 IV 23.6 (+) 0.5 (−) P13 IV 3.8 (−)21.5 (−) P14 IV 39.2 (+) 248000 (+) P17 IV 282.1 (+) 77700 (+) P18 IV14.8 (+) 7580 (+) P19 IIB 6.1 (+) 562 (+) P21 III 1.4 (−) 4690 (+) P25IV 255.7 (+) 302.9 (+) P26 IIB 3.9 (−) 0.1 (−) P27 III 1 (−) 1304 (+)P29 III 5.9 (+) 883 (+) P33 IV 3.6 (−) 3.7 (−) P35 IV 3.8 (−) 8600 (+)P38 IV 26.7 (+) 9080 (+) P39 IV 31.2 (+) 299000 (+) P42 IV 4.8 (−) 14.1(−) P43 IV 188.2 (+) 119700 (+) P44 IV 55.3 (+) 38620 (+) P46 IV 20.7(+) 10.6 (−) P47 IV 5.6 (+) 107.9 (+) P48 III 3.4 (−) 285.6 (+) P49 IIB3.6 (−) 338.8 (+) P50 III 11 (+) 2760 (+) P52 IV 13.6 (+) 9850 (+) P53III 8.8 (+) 891 (+) P54 III 8.4 (+) 0.5 (−) P55 IV 8.1 (+) 8799 (+) P56IV 202 (+) 337900 (+) P57 IV 1.8 (−) 110.7 (+) P59 IV 64.3 (+) 223.9 (+)P60 IIB 2.8 (−) 270.2 (+) P61 IIB 1 (−) 29.5 (−) P62 III 32.2 (+) 1490(+) P66 IIB 1.5 (−) 0.1 (−) P68 III 5.7 (+) 236.9 (+) P71 IIB 6.2 (+)742 (+) P72 IIB 3.2 (−) 81.4 (+) P73 IV 4.4 (−) 970 (+) P75 III 1.4 (−)580 (+) P76 III 59.9 (+) 1279 (+) P79 IV 2.6 (−) 1297 (+) P80 IV 8.4 (+)0.9 (−) P81 IV 4.1 (−) 882 (+) P83 IV 8.6 (+) 2.2 (−) P84 IV 2 (−) 1375(+) P86 III 4.3 (−) 17640 (+) P87 III 6.6 (+) 374.3 (+) P88 IV 147.4 (+)2695 (+) P89 IV 2.9 (−) 2274 (+) P90 IV 7.4 (+) 1986 (+) P93 IV 17.8 (+)2771 (+) P94 III 2 (−) 116.1 (+) P95 III 3.5 (−) 132.9 (+) P96 IV 1.2(−) 2.3 (−) P97 IV 338.1 (+) 42990 (+) P98 IV 1.5 (−) 57500 (+) P99 IV74.1 (+) 89700 (+) B38 IIB 0.9 (−) 19 (−) B87 III 5.7 (+) 0.1 (−) P101IV 43.2 (+) 91500 (+) Sensitivity (%) 55.2 77.6

TABLE 5-2 Validation cohort Sample name Cancer stage CEA (ng/mL) CA19-9(U/mL) P02 IV 1.5 (−) 569 (+) P03 III 4 (−) 1116 (+) P04 IV 4.6 (−) 5.8(−) P08 III 3.3 (−) 81.4 (+) P15 IV 12.8 (+) 47.1 (+) P16 IV 5.1 (+)181.4 (+) P20 III 0.9 (−) 13.6 (−) P22 III 0.7 (−) 31.4 (−) P23 IV 7.7(+) 17080 (+) P24 III 1.7 (−) 72.9 (+) P28 IV 25.1 (+) 2995 (+) P30 IV4.3 (−) 5.7 (−) P31 IV 2.9 (−) 3375 (+) P32 III 12.2 (+) 2955 (+) P34IIA 1.3 (−) 66 (+) P36 III 2.7 (−) 32.2 (−) P37 III 2 (−) 858 (+) P40III 65.6 (+) 9.6 (−) P41 IV 11.4 (+) 128080 (+) P45 III 2 (−) 410.8 (+)P51 IV 26.1 (+) 5880 (+) P58 IV 80.3 (+) 6510 (+) P63 IIB 4.4 (−) 5490(+) P65 IB 7 (+) 55.3 (+) P67 IIB 2.5 (−) 28.7 (−) P69 IIB 4.2 (−) 832(+) P70 IIB 1.6 (−) 71.3 (+) P74 IIA 3.2 (−) 36.8 (−) P77 IV 9.5 (+)6110 (+) P78 IV 417 (+) 971000 (+) P82 III 6.7 (+) 3730 (+) P85 IV 5.4(+) 6960 (+) P100 IV 240 (+) 68500 (+) Sensitivity (%) 45.5 75.8

For CEA, 5 ng/ml or lower was indicated as “−”, and, for CA19-9, 37 U/mlor lower was indicated as “−”, while values exceeding these wereindicated as “+”.

TABLE 6 Training cohort Validation cohort Accuracy SensitivitySpecificity Accuracy Sensitivity Specificity SEQ ID NO: (%) (%) (%) (%)(%) (%) 2_105 96.4 94 98 100 100 100 18_105 98.8 97 100 100 100 10046_105 97.6 95.5 99 100 100 100 55_105 98.2 97 99 100 100 100 58_10598.2 95.5 100 100 100 100 66_105 96.4 92.5 99 100 100 100 71_105 98.2 9799 100 100 100 77_105 98.8 97 100 100 100 100 83_105 97 95.5 98 100 100100 99_105 97 94 99 100 100 100 10_18 96.4 91 100 100 100 100 52_10596.4 94 98 98.8 100 98 18_109 97.6 95.5 99 98.8 100 98 18_25 88.6 79.195 97.6 100 96 25_112 89.2 80.6 95 97.6 100 96 8_109 95.8 94 97 96.4 10094 25_58 87.4 74.6 96 95.2 100 92 5_105 98.2 97 99 98.8 97 100 8_10597.6 95.5 99 98.8 97 100 13_105 98.2 95.5 100 98.8 97 100 35_105 97.695.5 99 98.8 97 100 70_105 97 94 99 98.8 97 100 74_105 97 95.5 98 98.897 100 79_105 97.6 95.5 99 98.8 97 100 89_105 97 94 99 98.8 97 10093_105 97 94 99 98.8 97 100 96_105 97 94 99 98.8 97 100 97_105 97.6 94100 98.8 97 100 18_107 97 94 99 98.8 97 100 18_108 97.6 94 100 98.8 97100 6_18 97.6 95.5 99 98.8 97 100 4_105 97 94 99 97.6 97 98 14_105 97.695.5 99 97.6 97 98 21_105 97 94 99 97.6 97 98 39_105 98.2 97 99 97.6 9798 56_105 97 95.5 98 97.6 97 98 68_105 97.6 95.5 99 97.6 97 98 94_105 9794 99 97.6 97 98 2_16 92.2 83.6 98 97.6 97 98 4_119 88 80.6 93 97.6 9798 12_108 93.4 89.4 96 97.6 97 98 83_108 92.2 83.6 98 97.6 97 98 5_3393.4 89.6 96 97.6 97 98 13_22 91.6 88.1 94 97.6 97 98 22_105 97 94 9996.4 97 96 2_10 92.2 83.6 98 96.4 97 96 2_22 90.4 82.1 96 96.4 97 9634_108 95.2 89.6 99 96.4 97 96 4_45 89.8 83.6 94 95.2 97 94 37_108 91.686.6 95 95.2 97 94 12_109 93.4 90.9 95 95.2 97 94 13_24 91.6 92.5 9195.2 97 94 18_70 88 77.6 95 95.2 97 94 25_83 83.8 74.6 90 95.2 97 9435_113 88.6 76.1 97 95.2 97 94 35_87 80.8 73.1 86 95.2 97 94 2_109 91.683.6 97 94 97 92 93_108 86.8 79.1 92 94 97 92 24_71 80.2 70.1 87 94 9792 24_35 84.4 73.1 92 92.8 97 90 4_98 86.7 75.8 94 91.6 97 88 13_25 9189.6 92 91.6 97 88 35_44 83.8 73.1 91 91.6 97 88 35_99 77.2 65.7 85 91.697 88 4_58 88 77.6 95 90.4 97 86 25_35 82 68.7 91 89.2 97 84 35_63 80.871.6 87 89.2 97 84 35_97 79.6 68.7 87 89.2 97 84 35_66 81.4 67.2 91 8897 82 35_121 81.4 67.2 91 88 97 82 35_94 77.8 61.2 89 86.7 97 80 66_10988 80.6 93 85.5 97 78 66_100 80.2 64.2 91 85.5 97 78 50_105 97 95.5 9898.8 96.9 100 23_105 97 94 99 97.6 96.9 98 35_50 80.2 67.2 89 89 96.9 841_77 95.8 91 99 96.3 96.8 96 6_105 96.4 94 98 97.6 93.9 100 7_105 97 9499 97.6 93.9 100 12_105 97.6 97 98 97.6 93.9 100 15_105 96.4 94 98 97.693.9 100 17_105 97 94 99 97.6 93.9 100 20_105 97.6 97 98 97.6 93.9 10025_105 96.4 94 98 97.6 93.9 100 26_105 97.6 97 98 97.6 93.9 100 27_10597 94 99 97.6 93.9 100 31_105 96.4 92.5 99 97.6 93.9 100 33_105 97 94 9997.6 93.9 100 34_105 95.8 92.5 98 97.6 93.9 100 40_105 96.4 94 98 97.693.9 100 49_105 97 97 97 97.6 93.9 100 57_105 97 94 99 97.6 93.9 10067_105 96.4 94 98 97.6 93.9 100 81_105 97.6 95.5 99 97.6 93.9 100 88_10597 94 99 97.6 93.9 100 90_105 97.6 95.5 99 97.6 93.9 100 98_105 96.493.9 98 97.6 93.9 100 1_119 97 95.5 98 97.6 93.9 100 2_108 95.2 88.1 10097.6 93.9 100 2_13 91.6 82.1 98 97.6 93.9 100 2_18 91 77.6 100 97.6 93.9100 2_34 90.4 79.1 98 97.6 93.9 100 2_35 88.6 74.6 98 97.6 93.9 100 2_3789.8 77.6 98 97.6 93.9 100 2_52 89.8 77.6 98 97.6 93.9 100 2_58 89.276.1 98 97.6 93.9 100 2_62 91 80.6 98 97.6 93.9 100 2_65 89.8 79.1 9797.6 93.9 100 2_71 89.2 76.1 98 97.6 93.9 100 2_119 90.4 80.6 97 97.693.9 100 2_120 88 76.1 96 97.6 93.9 100 2_121 88 74.6 97 97.6 93.9 1002_94 88.6 76.1 97 97.6 93.9 100 2_98 89.2 77.3 97 97.6 93.9 100 2_9988.6 74.6 98 97.6 93.9 100 4_13 95.2 89.6 99 97.6 93.9 100 58_108 95.288.1 100 97.6 93.9 100 6_8 94.6 91 97 97.6 93.9 100 9_105 97 94 99 96.493.9 98 24_105 97 94 99 96.4 93.9 98 28_105 97 94 99 96.4 93.9 98 29_10597 94 99 96.4 93.9 98 36_105 97 94 99 96.4 93.9 98 37_105 97.6 95.5 9996.4 93.9 98 38_105 97 94 99 96.4 93.9 98 43_105 97 95.5 98 96.4 93.9 9845_105 97 94 99 96.4 93.9 98 47_105 96.4 94 98 96.4 93.9 98 62_105 96.494 98 96.4 93.9 98 65_105 97.6 95.5 99 96.4 93.9 98 80_105 97 94 99 96.493.9 98 82_105 97 94 99 96.4 93.9 98 84_105 97 94 99 96.4 93.9 98 85_10596.4 94 98 96.4 93.9 98 86_105 97 94 99 96.4 93.9 98 92_105 95.8 92.5 9896.4 93.9 98 102_105 97 94 99 96.4 93.9 98 1_20 95.2 92.5 97 96.4 93.998 2_6 93.4 88.1 97 96.4 93.9 98 2_112 87.4 74.6 96 96.4 93.9 98 2_4590.4 79.1 98 96.4 93.9 98 2_80 88.6 74.6 98 96.4 93.9 98 2_81 88.6 75.897 96.4 93.9 98 2_88 90.4 79.1 98 96.4 93.9 98 13_107 96.4 91 100 96.493.9 98 4_18 89.8 77.6 98 96.4 93.9 98 5_19 92.2 85.1 97 96.4 93.9 987_34 91.6 83.6 97 96.4 93.9 98 16_105 97.6 95.5 99 95.2 93.9 96 51_10597 94 99 95.2 93.9 96 75_105 97.6 95.5 99 95.2 93.9 96 78_105 97 94 9995.2 93.9 96 100_105 97.6 95.5 99 95.2 93.9 96 104_105 97 94 99 95.293.9 96 1_2 96.4 92.5 99 95.2 93.9 96 1_12 95.8 92.4 98 95.2 93.9 961_37 95.2 94 96 95.2 93.9 96 2_21 90.4 77.6 99 95.2 93.9 96 2_67 89.277.6 97 95.2 93.9 96 2_78 89.2 79.1 96 95.2 93.9 96 2_103 89.8 77.6 9895.2 93.9 96 37_107 92.2 86.6 96 95.2 93.9 96 35_108 92.2 82.1 99 95.293.9 96 71_108 94.6 89.6 98 95.2 93.9 96 5_44 91 86.6 94 95.2 93.9 965_57 91.6 83.6 97 95.2 93.9 96 7_12 91.6 87.9 94 95.2 93.9 96 7_94 92.283.6 98 95.2 93.9 96 18_24 88.6 80.6 94 95.2 93.9 96 25_98 84.3 75.8 9095.2 93.9 96 30_35 86.2 80.6 90 95.2 93.9 96 3_105 95.8 94 97 94 93.9 942_54 89.2 77.6 97 94 93.9 94 5_107 94 91 96 94 93.9 94 4_112 88.6 76.197 94 93.9 94 74_108 91.6 86.6 95 94 93.9 94 5_18 91 80.6 98 94 93.9 945_30 95.8 94 97 94 93.9 94 7_18 93.4 86.6 98 94 93.9 94 7_37 90.4 83.695 94 93.9 94 13_42 89.8 85.1 93 94 93.9 94 22_24 86.8 82.1 90 94 93.994 35_115 82.6 70.1 91 94 93.9 94 12_107 95.2 93.9 96 92.8 93.9 92 4_1291 84.8 95 92.8 93.9 92 4_44 88 76.1 96 92.8 93.9 92 4_75 84.4 73.1 9292.8 93.9 92 4_120 86.8 76.1 94 92.8 93.9 92 4_97 89.2 82.1 94 92.8 93.992 13_108 93.4 89.6 96 92.8 93.9 92 97_108 95.2 94 96 92.8 93.9 92 5_3191.6 88.1 94 92.8 93.9 92 5_66 91 86.6 94 92.8 93.9 92 5_80 86.8 73.1 9692.8 93.9 92 6_112 93.4 91 95 92.8 93.9 92 7_119 91.6 86.6 95 92.8 93.992 9_35 83.8 73.1 91 92.8 93.9 92 10_13 90.4 88.1 92 92.8 93.9 92 18_3584.4 73.1 92 92.8 93.9 92 22_120 83.8 73.1 91 92.8 93.9 92 25_81 81.971.2 89 92.8 93.9 92 35_112 79 65.7 88 92.8 93.9 92 4_26 88.6 79.1 9591.6 93.9 90 4_49 90.4 82.1 96 91.6 93.9 90 4_63 88.6 80.6 94 91.6 93.990 4_71 88.6 79.1 95 91.6 93.9 90 37_109 89.2 80.6 95 91.6 93.9 90 7_1393.4 92.5 94 91.6 93.9 90 10_112 94 89.6 97 91.6 93.9 90 13_35 88.6 82.193 91.6 93.9 90 18_22 87.4 82.1 91 91.6 93.9 90 22_98 84.9 77.3 90 91.693.9 90 24_93 82 73.1 88 91.6 93.9 90 25_120 88.6 83.6 92 91.6 93.9 9035_47 80.2 70.1 87 91.6 93.9 90 35_65 80.2 70.1 87 91.6 93.9 90 34_10791.6 91 92 90.4 93.9 88 4_20 91 83.6 96 90.4 93.9 88 4_34 87.4 80.6 9290.4 93.9 88 4_46 88 76.1 96 90.4 93.9 88 4_65 89.8 82.1 95 90.4 93.9 884_89 89.8 80.6 96 90.4 93.9 88 13_66 86.8 82.1 90 90.4 93.9 88 24_11287.4 80.6 92 90.4 93.9 88 24_83 80.2 67.2 89 90.4 93.9 88 24_96 82.673.1 89 90.4 93.9 88 25_119 84.4 79.1 88 90.4 93.9 88 25_96 82.6 68.7 9290.4 93.9 88 31_119 84.4 76.1 90 90.4 93.9 88 35_53 79.6 64.2 90 90.493.9 88 35_55 79.6 59.7 93 90.4 93.9 88 35_119 80.8 68.7 89 90.4 93.9 8835_98 82.5 69.7 91 90.4 93.9 88 4_109 88 77.6 95 89.2 93.9 86 20_10994.6 92.5 96 89.2 93.9 86 22_35 83.2 74.6 89 89.2 93.9 86 22_58 83.271.6 91 89.2 93.9 86 22_100 83.2 74.6 89 89.2 93.9 86 35_89 82.6 70.1 9189.2 93.9 86 35_92 80.8 64.2 92 89.2 93.9 86 4_52 86.8 76.1 94 88 93.984 10_35 89.8 83.6 94 88 93.9 84 25_52 88 79.1 94 88 93.9 84 35_80 80.865.7 91 88 93.9 84 35_83 77.8 59.7 90 88 93.9 84 35_72 80.2 65.7 90 87.893.9 83.7 26_109 92.8 89.6 95 86.7 93.9 82 22_83 82 70.1 90 86.7 93.9 8225_99 83.2 71.6 91 86.7 93.9 82 35_79 79 64.2 89 86.7 93.9 82 10_52 90.486.6 93 85.5 93.9 80 25_79 81.4 68.7 90 85.5 93.9 80 1_23 97 95.5 9896.3 93.8 98 4_50 86.2 73.1 95 90.2 93.8 88 3_77 92.2 83.6 98 95.1 93.596 11_105 97 94 99 96.4 90.9 100 19_105 95.8 94 97 96.4 90.9 100 30_10597.6 95.5 99 96.4 90.9 100 41_105 96.4 94 98 96.4 90.9 100 44_105 97 9499 96.4 90.9 100 48_105 97 94 99 96.4 90.9 100 60_105 97 94 99 96.4 90.9100 73_105 96.4 94 98 96.4 90.9 100 87_105 97 94 99 96.4 90.9 100 1_1397 94 99 96.4 90.9 100 1_61 97 95.5 98 96.4 90.9 100 2_7 92.8 83.6 9996.4 90.9 100 2_15 94 86.6 99 96.4 90.9 100 2_19 92.2 83.6 98 96.4 90.9100 2_24 91 82.1 97 96.4 90.9 100 2_25 90.4 80.6 97 96.4 90.9 100 2_3090.4 82.1 96 96.4 90.9 100 2_44 89.8 79.1 97 96.4 90.9 100 2_46 88.674.6 98 96.4 90.9 100 2_53 91.6 80.6 99 96.4 90.9 100 2_55 88.6 74.6 9896.4 90.9 100 2_63 91 80.6 98 96.4 90.9 100 2_66 88.6 74.6 98 96.4 90.9100 2_70 88.6 74.6 98 96.4 90.9 100 2_73 90.4 80.6 97 96.4 90.9 100 2_7489.2 77.6 97 96.4 90.9 100 2_118 89.2 77.6 97 96.4 90.9 100 2_85 88 74.697 96.4 90.9 100 2_87 89.8 80.6 96 96.4 90.9 100 2_89 89.8 77.6 98 96.490.9 100 2_90 89.2 76.1 98 96.4 90.9 100 2_92 88.6 74.6 98 96.4 90.9 1002_93 88.6 74.6 98 96.4 90.9 100 2_96 88.6 76.1 97 96.4 90.9 100 2_100 8874.6 97 96.4 90.9 100 32_105 95.8 92.5 98 95.2 90.9 98 42_105 97 94 9995.2 90.9 98 53_105 96.4 94 98 95.2 90.9 98 54_105 96.4 94 98 95.2 90.998 63_105 97 94 99 95.2 90.9 98 64_105 96.4 94 98 95.2 90.9 98 69_105 9794 99 95.2 90.9 98 76_105 97 94 99 95.2 90.9 98 91_105 97 94 99 95.290.9 98 103_105 97 94 99 95.2 90.9 98 1_108 97 95.5 98 95.2 90.9 98 1_1897 92.5 100 95.2 90.9 98 1_30 95.2 91 98 95.2 90.9 98 1_36 96.4 94 9895.2 90.9 98 1_120 96.4 94 98 95.2 90.9 98 2_5 91 80.6 98 95.2 90.9 982_14 92.8 83.6 99 95.2 90.9 98 2_28 93.4 85.1 99 95.2 90.9 98 2_41 9182.1 97 95.2 90.9 98 2_116 89.2 77.6 97 95.2 90.9 98 2_117 89.2 77.6 9795.2 90.9 98 2_82 90.4 77.6 99 95.2 90.9 98 2_84 91 80.6 98 95.2 90.9 982_104 91 80.6 98 95.2 90.9 98 4_30 88.6 77.6 96 95.2 90.9 98 4_87 9179.1 99 95.2 90.9 98 8_108 96.4 92.5 99 95.2 90.9 98 98_108 95.2 87.9100 95.2 90.9 98 5_13 92.2 86.6 96 95.2 90.9 98 7_52 91 82.1 97 95.290.9 98 8_10 94.6 89.6 98 95.2 90.9 98 18_110 95.8 94 97 95.2 90.9 9818_111 89.2 79.1 96 95.2 90.9 98 19_35 86.8 77.6 93 95.2 90.9 98 19_5889.8 83.6 94 95.2 90.9 98 72_105 96.4 94 98 95.1 90.9 98 1_4 95.8 94 9794 90.9 96 1_8 96.4 94 98 94 90.9 96 1_110 96.4 94 98 94 90.9 96 1_14 9794 99 94 90.9 96 1_22 95.8 95.5 96 94 90.9 96 1_25 95.8 94 97 94 90.9 961_26 94.6 91 97 94 90.9 96 1_35 97 95.5 98 94 90.9 96 1_40 96.4 94 98 9490.9 96 1_112 95.8 91 99 94 90.9 96 1_43 95.2 91 98 94 90.9 96 1_49 95.892.5 98 94 90.9 96 1_113 95.8 92.5 98 94 90.9 96 1_52 97 94 99 94 90.996 1_55 96.4 94 98 94 90.9 96 1_56 96.4 95.5 97 94 90.9 96 1_58 95.892.5 98 94 90.9 96 1_65 96.4 94 98 94 90.9 96 1_66 94.6 91 97 94 90.9 961_69 97 94 99 94 90.9 96 1_71 98.2 98.5 98 94 90.9 96 1_74 95.8 92.5 9894 90.9 96 1_79 96.4 95.5 97 94 90.9 96 1_81 97 93.9 99 94 90.9 96 1_8396.4 94 98 94 90.9 96 1_99 97 94 99 94 90.9 96 1_102 97 95.5 98 94 90.996 8_106 94.6 88.1 99 94 90.9 96 2_107 93.4 86.6 98 94 90.9 96 2_4 89.279.1 96 94 90.9 96 2_9 92.8 85.1 98 94 90.9 96 2_12 91.6 81.8 98 94 90.996 2_111 92.2 83.6 98 94 90.9 96 2_39 88.6 74.6 98 94 90.9 96 2_114 89.274.6 99 94 90.9 96 2_69 90.4 80.6 97 94 90.9 96 2_95 89.2 77.6 97 9490.9 96 4_7 92.2 83.6 98 94 90.9 96 4_41 88 77.6 95 94 90.9 96 5_10895.2 91 98 94 90.9 96 21_108 92.2 85.1 97 94 90.9 96 49_108 92.8 86.6 9794 90.9 96 65_108 91.6 88.1 94 94 90.9 96 96_108 93.4 88.1 97 94 90.9 9699_108 94 86.6 99 94 90.9 96 13_109 94.6 89.6 98 94 90.9 96 7_67 91 83.696 94 90.9 96 7_70 92.8 86.6 97 94 90.9 96 9_119 87.4 83.6 90 94 90.9 9610_12 91.6 89.4 93 94 90.9 96 13_16 94.6 98.5 92 94 90.9 96 14_18 9488.1 98 94 90.9 96 35_41 83.2 73.1 90 94 90.9 96 66_85 83.2 68.7 93 9490.9 96 1_21 96.4 95.5 97 92.8 90.9 94 1_29 96.4 94 98 92.8 90.9 94 1_3997.6 97 98 92.8 90.9 94 1_70 97 94 99 92.8 90.9 94 1_75 97 94 99 92.890.9 94 4_107 90.4 85.1 94 92.8 90.9 94 14_107 92.2 80.6 100 92.8 90.994 58_107 92.8 88.1 96 92.8 90.9 94 66_107 90.4 80.6 97 92.8 90.9 9494_107 90.4 83.6 95 92.8 90.9 94 99_107 89.8 80.6 96 92.8 90.9 94 3_11991 89.6 92 92.8 90.9 94 4_14 90.4 82.1 96 92.8 90.9 94 4_113 90.4 80.697 92.8 90.9 94 4_115 89.8 79.1 97 92.8 90.9 94 43_108 93.4 91 95 92.890.9 94 5_7 95.2 94 96 92.8 90.9 94 5_12 91.6 84.8 96 92.8 90.9 94 5_2493.4 91 95 92.8 90.9 94 5_112 87.4 79.1 93 92.8 90.9 94 5_89 90.4 83.695 92.8 90.9 94 7_9 90.4 89.6 91 92.8 90.9 94 7_16 90.4 88.1 92 92.890.9 94 7_22 91 83.6 96 92.8 90.9 94 7_51 91 85.1 95 92.8 90.9 94 7_6291.6 85.1 96 92.8 90.9 94 7_114 89.8 83.6 94 92.8 90.9 94 7_80 92.2 85.197 92.8 90.9 94 7_83 91 80.6 98 92.8 90.9 94 7_103 91.6 86.6 95 92.890.9 94 10_20 89.8 85.1 93 92.8 90.9 94 10_58 94.6 91 97 92.8 90.9 9413_27 91 86.6 94 92.8 90.9 94 18_30 86.8 80.6 91 92.8 90.9 94 18_41 8577.6 90 92.8 90.9 94 18_66 85 74.6 92 92.8 90.9 94 22_85 86.2 77.6 9292.8 90.9 94 24_37 85 74.6 92 92.8 90.9 94 24_119 82.6 76.1 87 92.8 90.994 25_39 86.2 74.6 94 92.8 90.9 94 25_45 88.6 76.1 97 92.8 90.9 94 25_4685 73.1 93 92.8 90.9 94 1_121 98.2 97 99 91.6 90.9 92 20_107 95.2 92.597 91.6 90.9 92 26_107 95.8 94 97 91.6 90.9 92 49_107 94 91 96 91.6 90.992 3_58 94.6 91 97 91.6 90.9 92 4_5 91 83.6 96 91.6 90.9 92 4_6 90.480.6 97 91.6 90.9 92 4_10 91.6 86.6 95 91.6 90.9 92 4_24 87.4 76.1 9591.6 90.9 92 4_48 89.2 79.1 96 91.6 90.9 92 4_55 88.6 79.1 95 91.6 90.992 4_88 86.2 77.6 92 91.6 90.9 92 4_102 89.2 80.6 95 91.6 90.9 92 55_10891.6 83.6 97 91.6 90.9 92 5_25 91 86.6 94 91.6 90.9 92 5_42 91.6 86.6 9591.6 90.9 92 5_56 91.6 88.1 94 91.6 90.9 92 7_21 90.4 85.1 94 91.6 90.992 7_35 89.8 79.1 97 91.6 90.9 92 7_112 93.4 86.6 98 91.6 90.9 92 7_6591 86.6 94 91.6 90.9 92 7_66 91 85.1 95 91.6 90.9 92 7_79 89.8 83.6 9491.6 90.9 92 7_120 91 83.6 96 91.6 90.9 92 7_87 91.6 85.1 96 91.6 90.992 7_88 90.4 86.6 93 91.6 90.9 92 7_104 91 86.6 94 91.6 90.9 92 10_12091.6 85.1 96 91.6 90.9 92 13_21 89.8 86.6 92 91.6 90.9 92 18_46 83.274.6 89 91.6 90.9 92 22_96 80.8 70.1 88 91.6 90.9 92 24_79 82 68.7 9191.6 90.9 92 25_94 82.6 68.7 92 91.6 90.9 92 35_90 79.6 65.7 89 91.690.9 92 54_107 92.2 88.1 95 90.4 90.9 90 3_21 91 88.1 93 90.4 90.9 903_35 94.6 95.5 94 90.4 90.9 90 4_9 88 77.6 95 90.4 90.9 90 4_37 85.674.6 93 90.4 90.9 90 4_43 86.8 74.6 95 90.4 90.9 90 4_47 89.2 79.1 9690.4 90.9 90 4_56 88.6 79.1 95 90.4 90.9 90 4_74 86.8 74.6 95 90.4 90.990 47_108 91.6 83.6 97 90.4 90.9 90 94_108 91.6 82.1 98 90.4 90.9 905_11 91.6 86.6 95 90.4 90.9 90 5_21 91.6 85.1 96 90.4 90.9 90 5_75 88.683.6 92 90.4 90.9 90 7_109 93.4 86.6 98 90.4 90.9 90 7_44 92.2 85.1 9790.4 90.9 90 7_58 89.8 77.6 98 90.4 90.9 90 7_71 89.2 82.1 94 90.4 90.990 7_121 91 88.1 93 90.4 90.9 90 7_99 88.6 80.6 94 90.4 90.9 90 9_2489.2 83.6 93 90.4 90.9 90 9_58 88 80.6 93 90.4 90.9 90 10_34 91.6 88.194 90.4 90.9 90 10_119 91 88.1 93 90.4 90.9 90 18_67 88.6 80.6 94 90.490.9 90 18_79 85.6 76.1 92 90.4 90.9 90 21_25 84.4 73.1 92 90.4 90.9 9022_46 83.2 73.1 90 90.4 90.9 90 22_88 83.8 77.6 88 90.4 90.9 90 24_55 8570.1 95 90.4 90.9 90 24_80 77.8 64.2 87 90.4 90.9 90 24_81 84.9 77.3 9090.4 90.9 90 24_90 83.2 71.6 91 90.4 90.9 90 25_34 89.8 80.6 96 90.490.9 90 35_37 79 68.7 86 90.4 90.9 90 66_98 79.5 63.6 90 90.4 90.9 9052_107 92.2 89.6 94 89.2 90.9 88 4_25 88 79.1 94 89.2 90.9 88 4_80 86.874.6 95 89.2 90.9 88 4_81 86.7 75.8 94 89.2 90.9 88 4_82 86.8 74.6 9589.2 90.9 88 4_83 86.8 74.6 95 89.2 90.9 88 4_85 88 76.1 96 89.2 90.9 884_90 87.4 76.1 95 89.2 90.9 88 4_91 85.6 73.1 94 89.2 90.9 88 4_94 87.474.6 96 89.2 90.9 88 49_109 89.8 89.6 90 89.2 90.9 88 10_81 89.2 81.8 9489.2 90.9 88 10_83 89.2 82.1 94 89.2 90.9 88 10_121 89.2 83.6 93 89.290.9 88 22_80 83.2 74.6 89 89.2 90.9 88 24_31 83.2 68.7 93 89.2 90.9 8824_118 83.2 74.6 89 89.2 90.9 88 25_66 80.8 67.2 90 89.2 90.9 88 25_7082.6 68.7 92 89.2 90.9 88 25_75 82.6 73.1 89 89.2 90.9 88 25_80 84.473.1 92 89.2 90.9 88 28_35 82 71.6 89 89.2 90.9 88 4_11 86.8 79.1 92 8890.9 86 4_16 88 77.6 95 88 90.9 86 4_21 87.4 76.1 95 88 90.9 86 4_3989.2 79.1 96 88 90.9 86 4_76 86.8 73.1 96 88 90.9 86 4_92 85.6 73.1 9488 90.9 86 4_96 88 76.1 96 88 90.9 86 4_99 85.6 71.6 95 88 90.9 86 9_10988.6 79.1 95 88 90.9 86 54_109 88 83.6 91 88 90.9 86 9_46 88 85.1 90 8890.9 86 13_67 83.2 74.6 89 88 90.9 86 13_79 84.4 82.1 86 88 90.9 8616_83 83.8 82.1 85 88 90.9 86 22_55 81.4 73.1 87 88 90.9 86 24_121 83.273.1 90 88 90.9 86 25_92 82.6 71.6 90 88 90.9 86 35_71 78.4 62.7 89 8890.9 86 35_93 77.8 61.2 89 88 90.9 86 4_84 87.4 79.1 93 86.7 90.9 844_121 86.8 76.1 94 86.7 90.9 84 81_109 84.9 80.3 88 86.7 90.9 84 21_3580.8 70.1 88 86.7 90.9 84 21_75 80.2 70.1 87 86.7 90.9 84 21_83 80.874.6 85 86.7 90.9 84 21_89 79 70.1 85 86.7 90.9 84 21_97 81.4 71.6 8886.7 90.9 84 22_66 77.2 67.2 84 86.7 90.9 84 22_119 83.8 80.6 86 86.790.9 84 24_58 81.4 71.6 88 86.7 90.9 84 24_120 83.2 76.1 88 86.7 90.9 8431_112 82.6 73.1 89 86.7 90.9 84 35_118 81.4 67.2 91 86.7 90.9 84 35_12079 64.2 89 86.7 90.9 84 35_96 78.4 62.7 89 86.7 90.9 84 66_70 81.4 68.790 86.7 90.9 84 66_119 79 70.1 85 86.7 90.9 84 21_109 91 85.1 95 85.590.9 82 21_55 79.6 65.7 89 85.5 90.9 82 21_56 80.8 68.7 89 85.5 90.9 8222_78 78.4 68.7 85 85.5 90.9 82 35_42 82.6 65.7 94 85.5 90.9 82 35_8177.1 63.6 86 85.5 90.9 82 35_82 77.2 62.7 87 85.5 90.9 82 35_100 77.864.2 87 85.5 90.9 82 35_103 80.8 65.7 91 85.5 90.9 82 39_109 84.4 76.190 84.3 90.9 80 31_58 82.6 73.1 89 84.3 90.9 80 35_75 77.8 59.7 90 84.390.9 80 9_100 88.6 91 87 83.1 90.9 78 10_94 85 79.1 89 83.1 90.9 7821_71 80.8 71.6 87 83.1 90.9 78 79_109 85 73.1 93 81.9 90.9 76 99_10985.6 80.6 89 81.9 90.9 76 31_109 85 73.1 93 80.7 90.9 74 2_50 91 79.1 9996.3 90.6 100 1_50 96.4 94 98 93.9 90.6 96 7_50 91 83.6 96 93.9 90.6 962_23 91.6 82.1 98 92.7 90.6 94 18_23 89.8 82.1 95 92.7 90.6 94 5_50 9183.6 96 91.5 90.6 92 24_50 81.4 74.6 86 91.5 90.6 92 4_23 86.8 74.6 9587.8 90.6 86 22_50 83.2 76.1 88 87.8 90.6 86 50_109 88 82.1 92 80.5 90.674 2_77 88.6 74.6 98 96.3 90.3 100 7_77 88.6 82.1 93 95.1 90.3 98 4_7788 76.1 96 92.6 90.3 94 21_77 80.8 76.1 84 87.7 90.3 86 1_105 97 94 9995.2 87.9 100 61_105 97 94 99 95.2 87.9 100 1_19 95.2 91 98 95.2 87.9100 1_87 98.2 97 99 95.2 87.9 100 13_106 94 85.1 100 95.2 87.9 100 2_1191 82.1 97 95.2 87.9 100 2_17 92.2 83.6 98 95.2 87.9 100 2_29 91.6 82.198 95.2 87.9 100 2_33 92.8 85.1 98 95.2 87.9 100 2_38 92.8 85.1 98 95.287.9 100 2_47 88.6 76.1 97 95.2 87.9 100 2_49 88.6 77.6 96 95.2 87.9 1002_113 91.6 82.1 98 95.2 87.9 100 2_56 91 82.1 97 95.2 87.9 100 2_57 88.676.1 97 95.2 87.9 100 2_60 90.4 80.6 97 95.2 87.9 100 2_64 91 80.6 9895.2 87.9 100 2_68 90.4 79.1 98 95.2 87.9 100 2_115 91 80.6 98 95.2 87.9100 2_79 88.6 74.6 98 95.2 87.9 100 2_91 89.2 76.1 98 95.2 87.9 1002_101 89.2 76.1 98 95.2 87.9 100 37_111 84.4 71.6 93 95.2 87.9 100 2_7289.8 80.6 96 95.1 87.9 100 10_105 97.6 95.5 99 94 87.9 98 95_105 97 95.598 94 87.9 98 1_5 97.6 97 98 94 87.9 98 1_7 97.6 94 100 94 87.9 98 1_4195.8 92.5 98 94 87.9 98 1_54 95.8 92.5 98 94 87.9 98 1_97 96.4 94 98 9487.9 98 1_101 96.4 94 98 94 87.9 98 18_106 95.8 91 99 94 87.9 98 30_10692.8 82.1 100 94 87.9 98 2_3 96.4 91 100 94 87.9 98 2_26 88.6 76.1 97 9487.9 98 2_27 89.8 79.1 97 94 87.9 98 2_31 88.6 74.6 98 94 87.9 98 2_3292.2 82.1 99 94 87.9 98 2_40 92.2 82.1 99 94 87.9 98 2_51 91 80.6 98 9487.9 98 2_83 90.4 77.6 99 94 87.9 98 3_12 92.8 89.4 95 94 87.9 98 3_1895.2 89.6 99 94 87.9 98 4_19 89.2 77.6 97 94 87.9 98 7_108 92.8 85.1 9894 87.9 98 26_108 92.8 89.6 95 94 87.9 98 46_108 92.2 85.1 97 94 87.9 9889_108 89.2 82.1 94 94 87.9 98 5_15 92.2 83.6 98 94 87.9 98 5_38 91.683.6 97 94 87.9 98 6_37 89.8 82.1 95 94 87.9 98 7_45 92.2 83.6 98 9487.9 98 7_74 93.4 89.6 96 94 87.9 98 7_85 92.8 85.1 98 94 87.9 98 7_9691 80.6 98 94 87.9 98 18_38 89.8 80.6 96 94 87.9 98 18_59 92.2 85.1 9794 87.9 98 19_46 90.4 85.1 94 94 87.9 98 59_105 97 95.5 98 92.8 87.9 96101_105 97 95.5 98 92.8 87.9 96 1_106 95.8 94 97 92.8 87.9 96 1_3 96.494 98 92.8 87.9 96 1_6 95.8 94 97 92.8 87.9 96 1_9 96.4 94 98 92.8 87.996 1_10 97 94 99 92.8 87.9 96 1_11 95.8 94 97 92.8 87.9 96 1_16 97.6 9798 92.8 87.9 96 1_17 95.8 94 97 92.8 87.9 96 1_24 97 95.5 98 92.8 87.996 1_28 96.4 94 98 92.8 87.9 96 1_31 97.6 95.5 99 92.8 87.9 96 1_32 96.494 98 92.8 87.9 96 1_33 95.8 94 97 92.8 87.9 96 1_34 97 94 99 92.8 87.996 1_38 95.8 92.5 98 92.8 87.9 96 1_42 95.8 94 97 92.8 87.9 96 1_44 95.894 97 92.8 87.9 96 1_45 96.4 92.5 99 92.8 87.9 96 1_46 96.4 92.5 99 92.887.9 96 1_47 97 97 97 92.8 87.9 96 1_48 97 94 99 92.8 87.9 96 1_51 95.894 97 92.8 87.9 96 1_53 95.2 92.5 97 92.8 87.9 96 1_57 95.8 94 97 92.887.9 96 1_60 95.8 94 97 92.8 87.9 96 1_62 96.4 94 98 92.8 87.9 96 1_6395.8 94 97 92.8 87.9 96 1_64 95.8 94 97 92.8 87.9 96 1_114 95.2 91 9892.8 87.9 96 1_67 96.4 94 98 92.8 87.9 96 1_68 95.8 94 97 92.8 87.9 961_115 95.8 94 97 92.8 87.9 96 1_117 95.8 92.5 98 92.8 87.9 96 1_73 9795.5 98 92.8 87.9 96 1_76 95.8 94 97 92.8 87.9 96 1_118 97.6 95.5 9992.8 87.9 96 1_78 95.8 94 97 92.8 87.9 96 1_80 96.4 95.5 97 92.8 87.9 961_84 95.8 94 97 92.8 87.9 96 1_85 95.8 94 97 92.8 87.9 96 1_86 97 95.598 92.8 87.9 96 1_88 95.8 92.5 98 92.8 87.9 96 1_89 97 94 99 92.8 87.996 1_90 97 97 97 92.8 87.9 96 1_91 95.8 94 97 92.8 87.9 96 1_92 95.292.5 97 92.8 87.9 96 1_94 96.4 94 98 92.8 87.9 96 1_95 96.4 94 98 92.887.9 96 1_98 97 93.9 99 92.8 87.9 96 1_100 95.8 94 97 92.8 87.9 96 1_10396.4 95.5 97 92.8 87.9 96 1_104 95.8 94 97 92.8 87.9 96 2_20 90.4 79.198 92.8 87.9 96 2_36 91.6 82.1 98 92.8 87.9 96 2_42 91.6 83.6 97 92.887.9 96 2_59 91.6 82.1 98 92.8 87.9 96 35_107 88 79.1 94 92.8 87.9 9698_107 90.4 81.8 96 92.8 87.9 96 3_13 92.8 88.1 96 92.8 87.9 96 3_12090.4 85.1 94 92.8 87.9 96 3_99 92.2 86.6 96 92.8 87.9 96 5_17 91.6 86.695 92.8 87.9 96 5_26 91 85.1 95 92.8 87.9 96 5_115 91.6 91 92 92.8 87.996 5_97 91 83.6 96 92.8 87.9 96 7_10 92.2 86.6 96 92.8 87.9 96 7_20 9186.6 94 92.8 87.9 96 7_24 92.8 88.1 96 92.8 87.9 96 7_54 88.6 82.1 9392.8 87.9 96 7_76 89.8 83.6 94 92.8 87.9 96 7_118 93.4 86.6 98 92.8 87.996 7_91 91 83.6 96 92.8 87.9 96 7_102 92.8 88.1 96 92.8 87.9 96 9_1891.6 85.1 96 92.8 87.9 96 9_120 83.2 79.1 86 92.8 87.9 96 11_18 88 83.691 92.8 87.9 96 12_24 86.1 80.3 90 92.8 87.9 96 13_30 89.2 89.6 89 92.887.9 96 13_53 85 85.1 85 92.8 87.9 96 13_60 86.8 79.1 92 92.8 87.9 9614_24 88 77.6 95 92.8 87.9 96 18_19 88 80.6 93 92.8 87.9 96 42_119 7965.7 88 92.8 87.9 96 1_72 95.8 94 97 92.7 87.9 95.9 1_109 97 95.5 9891.6 87.9 94 1_59 95.2 91 98 91.6 87.9 94 1_116 95.8 92.5 98 91.6 87.994 1_93 97.6 95.5 99 91.6 87.9 94 2_106 93.4 85.1 99 91.6 87.9 94 9_10692.2 83.6 98 91.6 87.9 94 9_107 93.4 86.6 98 91.6 87.9 94 39_107 91 85.195 91.6 87.9 94 44_107 95.2 91 98 91.6 87.9 94 55_107 92.8 85.1 98 91.687.9 94 3_5 97 95.5 98 91.6 87.9 94 3_71 98.2 98.5 98 91.6 87.9 94 4_10893.4 88.1 97 91.6 87.9 94 4_8 92.8 85.1 98 91.6 87.9 94 20_108 93.4 89.696 91.6 87.9 94 70_108 90.4 79.1 98 91.6 87.9 94 81_108 92.2 84.8 9791.6 87.9 94 87_108 88 83.6 91 91.6 87.9 94 5_20 92.2 88.1 95 91.6 87.994 5_29 90.4 82.1 96 91.6 87.9 94 5_87 89.8 83.6 94 91.6 87.9 94 5_90 8882.1 92 91.6 87.9 94 14_109 87.4 74.6 96 91.6 87.9 94 7_47 86.8 80.6 9191.6 87.9 94 7_55 92.2 83.6 98 91.6 87.9 94 7_115 94 88.1 98 91.6 87.994 7_75 89.8 83.6 94 91.6 87.9 94 7_82 90.4 85.1 94 91.6 87.9 94 7_9290.4 83.6 95 91.6 87.9 94 7_93 91 82.1 97 91.6 87.9 94 7_97 91 83.6 9691.6 87.9 94 7_98 89.8 81.8 95 91.6 87.9 94 11_25 88 80.6 93 91.6 87.994 14_21 88.6 79.1 95 91.6 87.9 94 18_42 89.8 79.1 97 91.6 87.9 94 18_5189.2 83.6 93 91.6 87.9 94 18_115 85.6 76.1 92 91.6 87.9 94 19_21 87.476.1 95 91.6 87.9 94 19_34 88.6 83.6 92 91.6 87.9 94 28_39 85.6 74.6 9391.6 87.9 94 30_46 85 79.1 89 91.6 87.9 94 39_87 86.2 73.1 95 91.6 87.994 58_113 87.4 79.1 93 91.6 87.9 94 7_72 89.2 83.6 93 91.5 87.9 93.95_106 94 88.1 98 90.4 87.9 92 16_106 93.4 86.6 98 90.4 87.9 92 24_10789.2 82.1 94 90.4 87.9 92 74_107 93.4 88.1 97 90.4 87.9 92 96_107 89.882.1 95 90.4 87.9 92 3_55 93.4 91 95 90.4 87.9 92 3_83 93.4 92.5 94 90.487.9 92 4_22 88 77.6 95 90.4 87.9 92 4_86 91 83.6 96 90.4 87.9 92 9_10890.4 86.6 93 90.4 87.9 92 31_108 91 82.1 97 90.4 87.9 92 44_108 93.488.1 97 90.4 87.9 92 52_108 95.2 88.1 100 90.4 87.9 92 80_108 91 88.1 9390.4 87.9 92 7_28 92.2 91 93 90.4 87.9 92 7_117 93.4 88.1 97 90.4 87.992 7_78 92.8 86.6 97 90.4 87.9 92 7_81 90.4 83.3 95 90.4 87.9 92 7_90 9185.1 95 90.4 87.9 92 8_21 86.2 76.1 93 90.4 87.9 92 9_13 92.2 94 91 90.487.9 92 10_37 88 82.1 92 90.4 87.9 92 10_66 87.4 76.1 95 90.4 87.9 9213_31 87.4 82.1 91 90.4 87.9 92 13_114 86.2 85.1 87 90.4 87.9 92 13_10385.6 82.1 88 90.4 87.9 92 16_119 86.2 80.6 90 90.4 87.9 92 18_27 89.283.6 93 90.4 87.9 92 18_47 83.8 76.1 89 90.4 87.9 92 18_113 90.4 83.6 9590.4 87.9 92 18_56 87.4 79.1 93 90.4 87.9 92 22_45 87.4 79.1 93 90.487.9 92 22_97 83.2 79.1 86 90.4 87.9 92 24_32 84.4 77.6 89 90.4 87.9 9224_74 80.2 76.1 83 90.4 87.9 92 24_99 83.2 74.6 89 90.4 87.9 92 30_3484.4 77.6 89 90.4 87.9 92 35_39 78.4 61.2 90 90.4 87.9 92 66_112 83.871.6 92 90.4 87.9 92 51_58 85.6 74.6 93 90.4 87.9 92 65_107 92.8 85.1 9889.2 87.9 90 92_107 92.8 89.6 95 89.2 87.9 90 3_4 93.4 88.1 97 89.2 87.990 4_32 90.4 83.6 95 89.2 87.9 90 4_53 86.2 73.1 95 89.2 87.9 90 4_6987.4 79.1 93 89.2 87.9 90 4_117 88.6 77.6 96 89.2 87.9 90 4_79 86.8 74.695 89.2 87.9 90 4_101 86.8 77.6 93 89.2 87.9 90 42_108 89.2 80.6 95 89.287.9 90 45_108 94.6 89.6 98 89.2 87.9 90 5_34 89.8 86.6 92 89.2 87.9 905_96 87.4 77.6 94 89.2 87.9 90 6_58 91.6 83.6 97 89.2 87.9 90 87_10992.2 88.1 95 89.2 87.9 90 7_69 89.8 83.6 94 89.2 87.9 90 7_100 94 91 9689.2 87.9 90 9_20 89.8 89.6 90 89.2 87.9 90 9_25 84.4 77.6 89 89.2 87.990 9_55 86.2 77.6 92 89.2 87.9 90 10_98 89.8 89.4 90 89.2 87.9 90 11_11283.8 77.6 88 89.2 87.9 90 12_21 85.5 77.3 91 89.2 87.9 90 13_18 89.885.1 93 89.2 87.9 90 21_119 81.4 73.1 87 89.2 87.9 90 21_122 77.8 68.784 89.2 87.9 90 22_115 85 79.1 89 89.2 87.9 90 24_33 82 70.1 90 89.287.9 90 24_34 82.6 76.1 87 89.2 87.9 90 24_42 77.8 59.7 90 89.2 87.9 9024_66 83.2 68.7 93 89.2 87.9 90 24_70 83.8 71.6 92 89.2 87.9 90 24_8281.4 71.6 88 89.2 87.9 90 24_97 83.2 77.6 87 89.2 87.9 90 25_89 85 74.692 89.2 87.9 90 25_121 80.8 70.1 88 89.2 87.9 90 35_51 77.8 59.7 90 89.287.9 90 35_54 80.8 70.1 88 89.2 87.9 90 35_61 76 62.7 85 89.2 87.9 9035_85 77.2 62.7 87 89.2 87.9 90 59_112 86.8 76.1 94 89.2 87.9 90 67_11280.8 64.2 92 89.2 87.9 90 46_104 84.4 71.6 93 89.2 87.9 90 51_52 85 79.189 89.2 87.9 90 55_113 89.8 80.6 96 89.2 87.9 90 3_67 92.2 89.6 94 8887.9 88 3_94 91.6 86.6 95 88 87.9 88 4_31 86.2 73.1 95 88 87.9 88 4_3586.8 74.6 95 88 87.9 88 4_51 86.8 74.6 95 88 87.9 88 4_59 86.2 73.1 9588 87.9 88 4_62 88 74.6 97 88 87.9 88 4_114 87.4 74.6 96 88 87.9 88 4_6886.2 73.1 95 88 87.9 88 4_116 88.6 77.6 96 88 87.9 88 4_78 86.2 74.6 9488 87.9 88 4_93 86.8 76.1 94 88 87.9 88 4_103 86.8 74.6 95 88 87.9 884_104 86.8 74.6 95 88 87.9 88 75_108 91.6 82.1 98 88 87.9 88 5_35 89.280.6 95 88 87.9 88 6_21 89.8 79.1 97 88 87.9 88 9_70 86.8 79.1 92 8887.9 88 9_85 83.2 79.1 86 88 87.9 88 10_79 85 74.6 92 88 87.9 88 11_5581.4 71.6 88 88 87.9 88 16_112 88 83.6 91 88 87.9 88 18_21 86.8 77.6 9388 87.9 88 19_75 88.6 80.6 94 88 87.9 88 21_22 80.2 71.6 86 88 87.9 8821_111 83.8 73.1 91 88 87.9 88 21_45 85.6 83.6 87 88 87.9 88 21_115 80.270.1 87 88 87.9 88 22_112 87.4 76.1 95 88 87.9 88 22_62 83.2 70.1 92 8887.9 88 22_118 83.2 73.1 90 88 87.9 88 24_64 77.2 62.7 87 88 87.9 8824_65 83.2 76.1 88 88 87.9 88 24_75 81.4 70.1 89 88 87.9 88 25_93 83.273.1 90 88 87.9 88 27_120 82.6 77.6 86 88 87.9 88 35_46 78.4 62.7 89 8887.9 88 35_91 80.2 67.2 89 88 87.9 88 35_122 79 67.2 87 88 87.9 88 42_5883.2 71.6 91 88 87.9 88 70_112 82 67.2 92 88 87.9 88 79_112 80.8 67.2 9088 87.9 88 4_72 89.2 82.1 94 87.8 87.9 87.8 21_106 93.4 85.1 99 86.787.9 86 4_64 85.6 74.6 93 86.7 87.9 86 4_66 88 77.6 95 86.7 87.9 864_118 89.8 82.1 95 86.7 87.9 86 5_78 88.6 82.1 93 86.7 87.9 86 5_82 89.885.1 93 86.7 87.9 86 9_56 83.2 77.6 87 86.7 87.9 86 9_71 86.2 79.1 9186.7 87.9 86 9_94 85.6 77.6 91 86.7 87.9 86 11_35 80.8 70.1 88 86.7 87.986 16_35 85.6 80.6 89 86.7 87.9 86 21_24 85 74.6 92 86.7 87.9 86 21_3982.6 73.1 89 86.7 87.9 86 21_46 82.6 71.6 90 86.7 87.9 86 21_49 83.274.6 89 86.7 87.9 86 21_57 84.4 76.1 90 86.7 87.9 86 21_85 80.2 68.7 8886.7 87.9 86 22_52 84.4 77.6 89 86.7 87.9 86 22_65 86.8 82.1 90 86.787.9 86 22_114 82 77.6 85 86.7 87.9 86 22_94 81.4 71.6 88 86.7 87.9 8622_99 83.8 74.6 90 86.7 87.9 86 25_44 83.2 71.6 91 86.7 87.9 86 25_6586.2 80.6 90 86.7 87.9 86 25_67 80.8 70.1 88 86.7 87.9 86 29_31 85 74.692 86.7 87.9 86 35_58 82 68.7 91 86.7 87.9 86 35_70 79.6 61.2 92 86.787.9 86 35_84 79.6 67.2 88 86.7 87.9 86 55_115 83.2 71.6 91 86.7 87.9 8658_79 79 64.2 89 86.7 87.9 86 66_83 80.8 67.2 90 86.7 87.9 86 67_80 76.665.7 84 86.7 87.9 86 79_98 77.1 60.6 88 86.7 87.9 86 83_104 79 64.2 8986.7 87.9 86 4_36 87.4 76.1 95 85.5 87.9 84 4_100 86.8 74.6 95 85.5 87.984 5_109 93.4 89.6 96 85.5 87.9 84 16_109 90.4 86.6 93 85.5 87.9 8425_109 85.6 76.1 92 85.5 87.9 84 58_110 88 83.6 91 85.5 87.9 84 11_7180.8 74.6 85 85.5 87.9 84 21_65 79.6 70.1 86 85.5 87.9 84 21_68 81.470.1 89 85.5 87.9 84 21_74 83.2 71.6 91 85.5 87.9 84 21_118 84.4 79.1 8885.5 87.9 84 21_90 77.2 71.6 81 85.5 87.9 84 22_104 79 73.1 83 85.5 87.984 24_52 81.4 71.6 88 85.5 87.9 84 24_67 82 73.1 88 85.5 87.9 84 24_9280.2 70.1 87 85.5 87.9 84 34_75 80.2 76.1 83 85.5 87.9 84 35_104 79 62.790 85.5 87.9 84 81_104 80.1 65.2 90 85.5 87.9 84 35_109 85 73.1 93 84.387.9 82 104_109 88 80.6 93 84.3 87.9 82 10_99 88 82.1 92 84.3 87.9 8221_31 78.4 65.7 87 84.3 87.9 82 21_98 78.9 69.7 85 84.3 87.9 82 24_9884.9 77.3 90 84.3 87.9 82 24_100 77.2 61.2 88 84.3 87.9 82 25_100 82.671.6 90 84.3 87.9 82 31_34 84.4 76.1 90 84.3 87.9 82 31_120 82.6 74.6 8884.3 87.9 82 35_52 79 65.7 88 84.3 87.9 82 35_114 79.6 65.7 89 84.3 87.982 35_69 83.8 73.1 91 84.3 87.9 82 58_67 79 58.2 93 84.3 87.9 82 65_7874.9 65.7 81 84.3 87.9 82 66_94 77.8 56.7 92 84.3 87.9 82 29_109 83.873.1 91 83.1 87.9 80 90_109 88 80.6 93 83.1 87.9 80 21_34 83.8 74.6 9083.1 87.9 80 21_52 80.8 71.6 87 83.1 87.9 80 21_121 82 74.6 87 83.1 87.980 21_94 79.6 70.1 86 83.1 87.9 80 21_102 78.4 71.6 83 83.1 87.9 8031_98 78.9 68.2 86 83.1 87.9 80 66_93 77.8 59.7 90 83.1 87.9 80 34_10988.6 91 87 81.9 87.9 78 80_109 87.4 80.6 92 81.9 87.9 78 21_100 81.471.6 88 81.9 87.9 78 35_78 76.6 59.7 88 81.9 87.9 78 42_109 85 77.6 9080.7 87.9 76 75_109 83.8 76.1 89 80.7 87.9 76 96_109 85 80.6 88 80.787.9 76 103_109 86.8 80.6 91 80.7 87.9 76 10_92 89.2 86.6 91 80.7 87.976 52_109 88 85.1 90 79.5 87.9 74 50_79 74.3 56.7 86 86.6 87.5 86 23_3581.4 67.2 91 85.4 87.5 84 10_50 90.4 83.6 95 84.1 87.5 82 50_67 74.361.2 83 82.9 87.5 80 77_108 90.4 77.6 99 95.1 87.1 100 24_77 80.8 74.685 88.9 87.1 90 9_77 83.8 76.1 89 87.7 87.1 88 19_106 93.4 86.6 98 9484.8 100 87_106 92.2 83.6 98 94 84.8 100 2_8 92.2 85.1 97 94 84.8 1002_75 88.6 76.1 97 94 84.8 100 2_97 88 74.6 97 94 84.8 100 2_102 92.882.1 100 94 84.8 100 2_122 89.2 77.6 97 94 84.8 100 6_119 91.6 83.6 9794 84.8 100 7_8 93.4 85.1 99 94 84.8 100 7_32 91 82.1 97 94 84.8 1008_17 90.4 79.1 98 94 84.8 100 12_15 92.8 86.4 97 94 84.8 100 17_18 9182.1 97 94 84.8 100 1_107 95.8 92.5 98 92.8 84.8 98 1_122 96.4 94 9892.8 84.8 98 2_110 92.2 85.1 97 92.8 84.8 98 2_48 91.6 80.6 99 92.8 84.898 2_61 89.8 76.1 99 92.8 84.8 98 2_76 91.6 80.6 99 92.8 84.8 98 8_10797 94 99 92.8 84.8 98 3_66 92.8 86.6 97 92.8 84.8 98 90_108 88 80.6 9392.8 84.8 98 5_113 93.4 94 93 92.8 84.8 98 5_53 91 85.1 95 92.8 84.8 986_12 92.2 83.3 98 92.8 84.8 98 6_13 94 86.6 99 92.8 84.8 98 6_20 91.686.6 95 92.8 84.8 98 6_26 91 83.6 96 92.8 84.8 98 7_111 88.6 77.6 9692.8 84.8 98 7_57 89.8 79.1 97 92.8 84.8 98 7_101 91.6 88.1 94 92.8 84.898 8_9 92.2 89.6 94 92.8 84.8 98 13_17 89.2 79.1 96 92.8 84.8 98 14_5592.8 82.1 100 92.8 84.8 98 17_20 89.2 79.1 96 92.8 84.8 98 18_69 86.876.1 94 92.8 84.8 98 1_15 96.4 94 98 91.6 84.8 96 1_27 97 95.5 98 91.684.8 96 1_111 96.4 95.5 97 91.6 84.8 96 1_82 96.4 95.5 97 91.6 84.8 961_96 95.8 92.5 98 91.6 84.8 96 49_106 91.6 83.6 97 91.6 84.8 96 7_10794.6 88.1 99 91.6 84.8 96 16_107 93.4 91 95 91.6 84.8 96 22_107 89.883.6 94 91.6 84.8 96 83_107 89.2 80.6 95 91.6 84.8 96 85_107 87.4 77.694 91.6 84.8 96 87_107 93.4 88.1 97 91.6 84.8 96 101_107 90.4 79.1 9891.6 84.8 96 3_26 90.4 86.6 93 91.6 84.8 96 4_61 89.2 80.6 95 91.6 84.896 64_108 86.8 76.1 94 91.6 84.8 96 66_108 91.6 85.1 96 91.6 84.8 965_28 91.6 89.6 93 91.6 84.8 96 5_37 90.4 83.6 95 91.6 84.8 96 5_119 9182.1 97 91.6 84.8 96 30_109 92.8 86.6 97 91.6 84.8 96 7_11 91.6 83.6 9791.6 84.8 96 7_19 92.8 88.1 96 91.6 84.8 96 7_26 93.4 88.1 97 91.6 84.896 7_30 92.8 88.1 96 91.6 84.8 96 7_38 93.4 86.6 98 91.6 84.8 96 7_46 9182.1 97 91.6 84.8 96 7_86 89.8 83.6 94 91.6 84.8 96 11_13 89.2 82.1 9491.6 84.8 96 12_17 90.4 80.3 97 91.6 84.8 96 12_25 92.2 89.4 94 91.684.8 96 18_55 83.2 71.6 91 91.6 84.8 96 18_57 82.6 70.1 91 91.6 84.8 9622_30 85 77.6 90 91.6 84.8 96 24_26 82.6 76.1 87 91.6 84.8 96 24_30 87.477.6 94 91.6 84.8 96 35_60 83.8 68.7 94 91.6 84.8 96 41_112 84.4 80.6 8791.6 84.8 96 46_113 86.2 79.1 91 91.6 84.8 96 51_120 83.2 71.6 91 91.684.8 96 5_72 90.4 89.6 91 91.5 84.8 95.9 20_106 92.2 83.6 98 90.4 84.894 25_107 90.4 83.6 95 90.4 84.8 94 47_107 90.4 83.6 95 90.4 84.8 9489_107 91 80.6 98 90.4 84.8 94 103_107 89.2 79.1 96 90.4 84.8 94 104_10791 83.6 96 90.4 84.8 94 4_33 88 76.1 96 90.4 84.8 94 4_38 86.2 74.6 9490.4 84.8 94 4_40 88.6 77.6 96 90.4 84.8 94 19_108 91.6 83.6 97 90.484.8 94 24_108 89.8 83.6 94 90.4 84.8 94 5_49 91 85.1 95 90.4 84.8 945_68 89.2 83.6 93 90.4 84.8 94 5_74 89.2 82.1 94 90.4 84.8 94 6_46 85.673.1 94 90.4 84.8 94 7_25 91 86.6 94 90.4 84.8 94 7_27 90.4 83.6 95 90.484.8 94 7_39 91 80.6 98 90.4 84.8 94 7_53 91 86.6 94 90.4 84.8 94 7_6490.4 83.6 95 90.4 84.8 94 7_122 91.6 86.6 95 90.4 84.8 94 9_117 85.679.1 90 90.4 84.8 94 13_40 86.2 79.1 91 90.4 84.8 94 14_35 88 79.1 9490.4 84.8 94 18_40 89.2 77.6 97 90.4 84.8 94 20_24 86.2 80.6 90 90.484.8 94 22_34 87.4 82.1 91 90.4 84.8 94 22_44 85.6 77.6 91 90.4 84.8 9424_25 82 67.2 92 90.4 84.8 94 24_40 82 73.1 88 90.4 84.8 94 25_56 81.473.1 87 90.4 84.8 94 25_85 82 76.1 86 90.4 84.8 94 27_112 86.2 80.6 9090.4 84.8 94 30_58 85 80.6 88 90.4 84.8 94 30_79 85 80.6 88 90.4 84.8 9430_81 82.5 72.7 89 90.4 84.8 94 33_35 82.6 67.2 93 90.4 84.8 94 35_4084.4 68.7 95 90.4 84.8 94 35_86 84.4 76.1 90 90.4 84.8 94 37_46 79.671.6 85 90.4 84.8 94 38_112 86.8 77.6 93 90.4 84.8 94 41_58 85.6 80.6 8990.4 84.8 94 46_53 84.4 74.6 91 90.4 84.8 94 46_115 82.6 73.1 89 90.484.8 94 46_87 79.6 73.1 84 90.4 84.8 94 53_94 82 71.6 89 90.4 84.8 9458_60 85 77.6 90 90.4 84.8 94 21_107 92.8 85.1 98 89.2 84.8 92 31_107 9180.6 98 89.2 84.8 92 67_107 89.8 82.1 95 89.2 84.8 92 79_107 89.8 79.197 89.2 84.8 92 95_107 92.2 85.1 97 89.2 84.8 92 97_107 91 83.6 96 89.284.8 92 100_107 89.8 79.1 97 89.2 84.8 92 3_112 93.4 89.6 96 89.2 84.892 3_81 94.6 90.9 97 89.2 84.8 92 4_28 88 77.6 95 89.2 84.8 92 53_108 8876.1 96 89.2 84.8 92 54_108 89.2 80.6 95 89.2 84.8 92 63_108 85.6 79.190 89.2 84.8 92 85_108 89.8 83.6 94 89.2 84.8 92 88_108 91 82.1 97 89.284.8 92 103_108 88.6 82.1 93 89.2 84.8 92 5_9 93.4 94 93 89.2 84.8 925_10 94 91 96 89.2 84.8 92 5_16 92.2 91 93 89.2 84.8 92 5_45 91 86.6 9489.2 84.8 92 5_51 89.8 86.6 92 89.2 84.8 92 5_104 91 83.6 96 89.2 84.892 7_31 90.4 86.6 93 89.2 84.8 92 7_42 91 83.6 96 89.2 84.8 92 7_84 90.485.1 94 89.2 84.8 92 7_95 92.2 86.6 96 89.2 84.8 92 9_112 91 88.1 9389.2 84.8 92 9_116 85 79.1 89 89.2 84.8 92 10_26 88.6 82.1 93 89.2 84.892 10_71 90.4 85.1 94 89.2 84.8 92 13_113 88 86.6 89 89.2 84.8 92 13_5685.6 80.6 89 89.2 84.8 92 15_34 88 82.1 92 89.2 84.8 92 16_24 89.8 85.193 89.2 84.8 92 17_35 85.6 70.1 96 89.2 84.8 92 17_112 90.4 82.1 96 89.284.8 92 18_31 86.2 76.1 93 89.2 84.8 92 18_53 87.4 79.1 93 89.2 84.8 9218_68 88.6 79.1 95 89.2 84.8 92 18_100 86.2 77.6 92 89.2 84.8 92 21_3781.4 70.1 89 89.2 84.8 92 24_103 80.2 67.2 89 89.2 84.8 92 25_111 86.276.1 93 89.2 84.8 92 25_117 85 74.6 92 89.2 84.8 92 25_90 80.2 67.2 8989.2 84.8 92 29_35 86.2 73.1 95 89.2 84.8 92 37_55 79 68.7 86 89.2 84.892 38_99 86.2 76.1 93 89.2 84.8 92 58_115 84.4 73.1 92 89.2 84.8 9245_107 91 83.6 96 88 84.8 90 3_108 91.6 85.1 96 88 84.8 90 3_39 93.489.6 96 88 84.8 90 4_27 88.6 77.6 96 88 84.8 90 4_54 88.6 77.6 96 8884.8 90 4_95 85.6 73.1 94 88 84.8 90 4_122 85.6 71.6 95 88 84.8 9025_108 90.4 83.6 95 88 84.8 90 48_108 87.4 77.6 94 88 84.8 90 59_108 8882.1 92 88 84.8 90 62_108 89.2 80.6 95 88 84.8 90 86_108 86.8 73.1 96 8884.8 90 5_22 91 86.6 94 88 84.8 90 5_36 91.6 88.1 94 88 84.8 90 5_11191.6 86.6 95 88 84.8 90 5_39 89.2 80.6 95 88 84.8 90 5_52 90.4 82.1 9688 84.8 90 5_79 88.6 83.6 92 88 84.8 90 9_12 91 87.9 93 88 84.8 90 9_2184.4 77.6 89 88 84.8 90 9_22 83.8 79.1 87 88 84.8 90 9_89 87.4 82.1 9188 84.8 90 10_89 88 80.6 93 88 84.8 90 11_37 86.2 82.1 89 88 84.8 9013_46 84.4 76.1 90 88 84.8 90 13_121 83.2 77.6 87 88 84.8 90 16_18 8883.6 91 88 84.8 90 18_34 86.2 80.6 90 88 84.8 90 18_75 85.6 82.1 88 8884.8 90 18_81 85.5 78.8 90 88 84.8 90 20_35 83.8 74.6 90 88 84.8 9021_41 81.4 73.1 87 88 84.8 90 21_113 82.6 73.1 89 88 84.8 90 24_39 82.670.1 91 88 84.8 90 28_46 86.8 77.6 93 88 84.8 90 34_41 83.2 79.1 86 8884.8 90 34_113 85 74.6 92 88 84.8 90 35_48 86.8 79.1 92 88 84.8 9035_102 80.8 70.1 88 88 84.8 90 44_111 79.6 62.7 91 88 84.8 90 46_11276.6 62.7 86 88 84.8 90 47_112 81.4 76.1 85 88 84.8 90 46_70 75.4 61.285 88 84.8 90 46_89 78.4 65.7 87 88 84.8 90 55_65 83.2 67.2 94 88 84.890 58_70 77.8 62.7 88 88 84.8 90 66_75 78.4 62.7 89 88 84.8 90 80_8372.5 53.7 85 88 84.8 90 25_106 88.6 79.1 95 86.7 84.8 88 34_106 89.280.6 95 86.7 84.8 88 3_34 91.6 86.6 95 86.7 84.8 88 3_121 94 92.5 9586.7 84.8 88 3_96 93.4 89.6 96 86.7 84.8 88 4_42 86.8 76.1 94 86.7 84.888 4_57 88.6 79.1 95 86.7 84.8 88 4_67 86.8 74.6 95 86.7 84.8 88 4_7086.8 73.1 96 86.7 84.8 88 79_108 90.4 79.1 98 86.7 84.8 88 6_52 87.480.6 92 86.7 84.8 88 6_99 86.8 79.1 92 86.7 84.8 88 40_109 86.8 77.6 9386.7 84.8 88 9_11 88 80.6 93 86.7 84.8 88 9_37 85 79.1 89 86.7 84.8 889_45 86.8 83.6 89 86.7 84.8 88 9_98 84.3 80.3 87 86.7 84.8 88 10_22 84.477.6 89 86.7 84.8 88 10_55 86.8 83.6 89 86.7 84.8 88 11_39 79.6 71.6 8586.7 84.8 88 11_46 79 68.7 86 86.7 84.8 88 11_75 81.4 73.1 87 86.7 84.888 13_63 88.6 91 87 86.7 84.8 88 13_81 84.3 81.8 86 86.7 84.8 88 16_4684.4 82.1 86 86.7 84.8 88 16_58 84.4 82.1 86 86.7 84.8 88 16_120 84.477.6 89 86.7 84.8 88 17_34 84.4 73.1 92 86.7 84.8 88 18_78 82.6 76.1 8786.7 84.8 88 18_84 88.6 79.1 95 86.7 84.8 88 21_26 83.2 70.1 92 86.784.8 88 21_33 82.6 74.6 88 86.7 84.8 88 21_42 85 71.6 94 86.7 84.8 8821_43 82.6 71.6 90 86.7 84.8 88 22_25 82 76.1 86 86.7 84.8 88 22_75 80.268.7 88 86.7 84.8 88 22_89 82.6 76.1 87 86.7 84.8 88 22_121 82 70.1 9086.7 84.8 88 24_44 81.4 70.1 89 86.7 84.8 88 24_46 82.6 74.6 88 86.784.8 88 25_118 84.4 74.6 91 86.7 84.8 88 34_35 79.6 70.1 86 86.7 84.8 8835_49 84.4 77.6 89 86.7 84.8 88 51_83 82 67.2 92 86.7 84.8 88 56_66 83.874.6 90 86.7 84.8 88 58_66 83.8 68.7 94 86.7 84.8 88 70_104 79.6 67.2 8886.7 84.8 88 24_72 79 65.7 88 86.6 84.8 87.8 31_106 89.8 77.6 98 85.584.8 86 71_106 89.8 79.1 97 85.5 84.8 86 99_106 89.8 77.6 98 85.5 84.886 76_108 85.6 79.1 90 85.5 84.8 86 21_110 89.2 85.1 92 85.5 84.8 869_34 86.8 80.6 91 85.5 84.8 86 9_83 83.8 74.6 90 85.5 84.8 86 9_102 86.280.6 90 85.5 84.8 86 10_39 91 86.6 94 85.5 84.8 86 11_24 83.2 76.1 8885.5 84.8 86 11_31 83.8 73.1 91 85.5 84.8 86 11_66 80.8 68.7 89 85.584.8 86 11_85 79.6 70.1 86 85.5 84.8 86 11_88 77.2 71.6 81 85.5 84.8 8613_47 89.8 85.1 93 85.5 84.8 86 16_89 85 79.1 89 85.5 84.8 86 21_48 82.674.6 88 85.5 84.8 86 22_39 83.2 73.1 90 85.5 84.8 86 22_51 82 76.1 8685.5 84.8 86 22_67 79 64.2 89 85.5 84.8 86 22_71 81.4 70.1 89 85.5 84.886 22_103 78.4 70.1 84 85.5 84.8 86 24_45 84.4 74.6 91 85.5 84.8 8624_85 76.6 64.2 85 85.5 84.8 86 24_89 83.2 80.6 85 85.5 84.8 86 25_55 8571.6 94 85.5 84.8 86 25_57 86.2 77.6 92 85.5 84.8 86 25_71 83.2 70.1 9285.5 84.8 86 25_104 81.4 71.6 88 85.5 84.8 86 28_71 86.8 80.6 91 85.584.8 86 31_39 82 70.1 90 85.5 84.8 86 34_111 80.8 73.1 86 85.5 84.8 8635_117 77.8 58.2 91 85.5 84.8 86 35_76 81.4 65.7 92 85.5 84.8 86 44_4679 68.7 86 85.5 84.8 86 46_80 78.4 61.2 90 85.5 84.8 86 66_78 76 61.2 8685.5 84.8 86 66_88 79 65.7 88 85.5 84.8 86 70_119 75.4 62.7 84 85.5 84.886 70_98 80.7 63.6 92 85.5 84.8 86 79_89 80.8 65.7 91 85.5 84.8 86103_106 89.2 79.1 96 84.3 84.8 84 3_78 88.6 83.6 92 84.3 84.8 84 32_10987.4 77.6 94 84.3 84.8 84 35_110 85.6 74.6 93 84.3 84.8 84 9_75 83.876.1 89 84.3 84.8 84 10_74 86.2 80.6 90 84.3 84.8 84 11_79 80.2 70.1 8784.3 84.8 84 11_98 81.9 74.2 87 84.3 84.8 84 16_21 85 77.6 90 84.3 84.884 20_67 84.4 77.6 89 84.3 84.8 84 21_59 82 74.6 87 84.3 84.8 84 21_12079.6 71.6 85 84.3 84.8 84 21_86 79.6 73.1 84 84.3 84.8 84 21_96 77.268.7 83 84.3 84.8 84 21_99 82.6 77.6 86 84.3 84.8 84 22_92 86.2 82.1 8984.3 84.8 84 22_93 82 68.7 91 84.3 84.8 84 24_94 79 62.7 90 84.3 84.8 8431_35 77.2 61.2 88 84.3 84.8 84 32_35 84.4 74.6 91 84.3 84.8 84 34_42 7970.1 85 84.3 84.8 84 35_57 79 58.2 93 84.3 84.8 84 42_94 77.8 55.2 9384.3 84.8 84 44_70 83.8 73.1 91 84.3 84.8 84 55_67 81.4 64.2 93 84.384.8 84 66_99 75.4 58.2 87 84.3 84.8 84 79_94 76.6 59.7 88 84.3 84.8 8482_83 72.5 52.2 86 84.3 84.8 84 93_106 89.2 76.1 98 83.1 84.8 82 51_10986.8 76.1 94 83.1 84.8 82 53_109 91.6 88.1 94 83.1 84.8 82 58_109 86.280.6 90 83.1 84.8 82 10_44 87.4 82.1 91 83.1 84.8 82 10_96 90.4 88.1 9283.1 84.8 82 11_21 81.4 74.6 86 83.1 84.8 82 11_70 79.6 68.7 87 83.184.8 82 11_83 79 68.7 86 83.1 84.8 82 21_44 82 71.6 89 83.1 84.8 8221_58 81.4 70.1 89 83.1 84.8 82 21_70 80.8 68.7 89 83.1 84.8 82 24_5681.4 77.6 84 83.1 84.8 82 25_31 80.8 65.7 91 83.1 84.8 82 25_103 82 70.190 83.1 84.8 82 27_34 83.8 77.6 88 83.1 84.8 82 35_64 79 65.7 88 83.184.8 82 44_79 82.6 65.7 94 83.1 84.8 82 55_79 78.4 62.7 89 83.1 84.8 8255_103 77.2 64.2 86 83.1 84.8 82 67_89 73.1 52.2 87 83.1 84.8 82 70_9476 61.2 86 83.1 84.8 82 79_119 75.4 64.2 83 83.1 84.8 82 83_103 71.350.7 85 83.1 84.8 82 3_109 92.2 89.6 94 81.9 84.8 80 100_108 89.8 83.694 81.9 84.8 80 22_109 86.2 77.6 92 81.9 84.8 80 24_109 84.4 79.1 8881.9 84.8 80 46_109 83.8 73.1 91 81.9 84.8 80 55_109 83.8 76.1 89 81.984.8 80 85_109 83.2 77.6 87 81.9 84.8 80 11_16 89.2 83.6 93 81.9 84.8 8011_78 79.6 71.6 85 81.9 84.8 80 11_121 80.2 70.1 87 81.9 84.8 80 11_9278.4 68.7 85 81.9 84.8 80 11_103 79.6 67.2 88 81.9 84.8 80 21_63 83.274.6 89 81.9 84.8 80 21_67 81.4 68.7 90 81.9 84.8 80 21_79 80.2 73.1 8581.9 84.8 80 21_81 80.1 72.7 85 81.9 84.8 80 21_84 83.2 73.1 90 81.984.8 80 21_92 80.2 71.6 86 81.9 84.8 80 21_93 78.4 71.6 83 81.9 84.8 8028_75 81.4 73.1 87 81.9 84.8 80 42_52 79 59.7 92 81.9 84.8 80 81_94 75.957.6 88 81.9 84.8 80 94_121 72.5 53.7 85 81.9 84.8 80 21_72 79.6 70.1 8681.7 84.8 79.6 47_109 85.6 79.1 90 80.7 84.8 78 56_109 82.6 76.1 87 80.784.8 78 62_109 86.8 77.6 93 80.7 84.8 78 82_109 85.6 76.1 92 80.7 84.878 88_109 85.6 83.6 87 80.7 84.8 78 89_109 85 77.6 90 80.7 84.8 7813_104 88.6 89.6 88 80.7 84.8 78 29_75 82 74.6 87 80.7 84.8 78 29_7983.2 74.6 89 80.7 84.8 78 31_45 85.6 79.1 90 80.7 84.8 78 79_99 74.355.2 87 80.7 84.8 78 104_121 77.8 67.2 85 80.7 84.8 78 67_109 84.4 74.691 79.5 84.8 76 94_109 82.6 76.1 87 79.5 84.8 76 98_109 88 84.8 90 79.584.8 76 31_78 80.2 67.2 89 79.5 84.8 76 83_109 83.8 76.1 89 78.3 84.8 7479_80 75.4 58.2 87 78.3 84.8 74 92_109 85.6 83.6 87 77.1 84.8 72 31_10079.6 70.1 86 77.1 84.8 72 25_50 85.6 74.6 93 91.5 84.4 96 23_107 88 77.695 90.2 84.4 94 7_23 91 85.1 95 90.2 84.4 94 14_50 86.2 73.1 95 90.284.4 94 50_108 89.8 80.6 96 87.8 84.4 90 50_107 89.8 80.6 96 86.6 84.488 5_23 91 86.6 94 85.4 84.4 86 50_112 76 62.7 85 85.4 84.4 86 50_7177.2 65.7 85 85.4 84.4 86 16_50 84.4 79.1 88 84.1 84.4 84 21_50 82 74.687 84.1 84.4 84 50_100 74.9 59.7 85 82.9 84.4 82 50_70 77.2 62.7 87 81.784.4 80 50_55 78.4 62.7 89 80.5 84.4 78 10_77 89.8 79.1 97 92.6 83.9 9877_106 92.2 82.1 99 91.4 83.9 96 22_77 85.6 77.6 91 90.1 83.9 94 25_7785 73.1 93 90.1 83.9 94 35_77 77.2 64.2 86 88.9 83.9 92 77_109 86.2 82.189 86.4 83.9 88 28_77 82.6 76.1 87 86.4 83.9 88 5_77 88 85.1 90 85.283.9 86 6_7 91.6 82.1 98 92.8 81.8 100 6_49 89.8 86.6 92 92.8 81.8 1007_17 89.8 77.6 98 92.8 81.8 100 8_111 90.4 79.1 98 92.8 81.8 100 13_1588.6 82.1 93 92.8 81.8 100 15_20 88.6 83.6 92 92.8 81.8 100 15_112 89.882.1 95 92.8 81.8 100 17_119 87.4 74.6 96 92.8 81.8 100 17_87 86.2 71.696 92.8 81.8 100 2_43 88.6 77.6 96 91.6 81.8 98 5_14 93.4 88.1 97 91.681.8 98 7_14 93.4 88.1 97 91.6 81.8 98 7_33 91 82.1 97 91.6 81.8 98 7_4890.4 85.1 94 91.6 81.8 98 7_59 90.4 82.1 96 91.6 81.8 98 7_89 91.6 83.697 91.6 81.8 98 8_110 93.4 89.6 96 91.6 81.8 98 8_14 89.8 77.6 98 91.681.8 98 11_87 86.8 74.6 95 91.6 81.8 98 13_19 90.4 88.1 92 91.6 81.8 9813_96 86.2 74.6 94 91.6 81.8 98 14_66 82.6 65.7 94 91.6 81.8 98 14_80 8568.7 96 91.6 81.8 98 14_96 86.8 77.6 93 91.6 81.8 98 15_25 87.4 73.1 9791.6 81.8 98 15_65 86.2 76.1 93 91.6 81.8 98 17_26 88.6 79.1 95 91.681.8 98 18_76 92.8 91 94 91.6 81.8 98 19_45 85 71.6 94 91.6 81.8 9819_70 88 82.1 92 91.6 81.8 98 19_83 86.2 82.1 89 91.6 81.8 98 24_11783.8 67.2 95 91.6 81.8 98 12_106 94 86.4 99 90.4 81.8 96 38_106 90.480.6 97 90.4 81.8 96 28_107 93.4 86.6 98 90.4 81.8 96 36_107 88 76.1 9690.4 81.8 96 38_107 91.6 82.1 98 90.4 81.8 96 41_107 91 83.6 96 90.481.8 96 51_107 88.6 77.6 96 90.4 81.8 96 59_107 88.6 77.6 96 90.4 81.896 68_107 88 76.1 96 90.4 81.8 96 70_107 88 76.1 96 90.4 81.8 96 75_10789.8 77.6 98 90.4 81.8 96 82_107 89.2 79.1 96 90.4 81.8 96 3_8 94.6 92.596 90.4 81.8 96 3_20 91 86.6 94 90.4 81.8 96 14_108 88.6 77.6 96 90.481.8 96 39_108 94 89.6 97 90.4 81.8 96 5_40 91.6 88.1 94 90.4 81.8 965_41 94 89.6 97 90.4 81.8 96 5_60 92.2 89.6 94 90.4 81.8 96 6_16 88.682.1 93 90.4 81.8 96 6_38 88.6 74.6 98 90.4 81.8 96 6_74 87.4 76.1 9590.4 81.8 96 6_120 88 79.1 94 90.4 81.8 96 7_29 92.8 85.1 98 90.4 81.896 7_43 92.8 89.6 95 90.4 81.8 96 7_113 94.6 89.6 98 90.4 81.8 96 7_7391 85.1 95 90.4 81.8 96 8_25 92.2 83.6 98 90.4 81.8 96 8_59 91 82.1 9790.4 81.8 96 10_30 87.4 76.1 95 90.4 81.8 96 11_30 88 80.6 93 90.4 81.896 11_119 82.6 73.1 89 90.4 81.8 96 13_111 85.6 73.1 94 90.4 81.8 9614_42 87.4 71.6 98 90.4 81.8 96 14_46 86.2 73.1 95 90.4 81.8 96 15_3183.8 68.7 94 90.4 81.8 96 15_35 86.2 73.1 95 90.4 81.8 96 15_94 85 73.193 90.4 81.8 96 17_37 85.6 73.1 94 90.4 81.8 96 18_48 88.6 79.1 95 90.481.8 96 18_89 85.6 79.1 90 90.4 81.8 96 19_39 92.2 83.6 98 90.4 81.8 9619_93 85 74.6 92 90.4 81.8 96 19_96 87.4 80.6 92 90.4 81.8 96 24_60 79.662.7 91 90.4 81.8 96 30_120 83.2 76.1 88 90.4 81.8 96 26_106 91.6 83.697 89.2 81.8 94 40_106 90.4 77.6 99 89.2 81.8 94 53_106 92.2 83.6 9889.2 81.8 94 10_107 88.6 77.6 96 89.2 81.8 94 15_107 90.4 77.6 99 89.281.8 94 17_107 88.6 76.1 97 89.2 81.8 94 29_107 89.2 79.1 96 89.2 81.894 40_107 91.6 80.6 99 89.2 81.8 94 43_107 92.8 89.6 95 89.2 81.8 9446_107 89.8 77.6 98 89.2 81.8 94 56_107 89.2 79.1 96 89.2 81.8 94 60_10790.4 79.1 98 89.2 81.8 94 62_107 91.6 83.6 97 89.2 81.8 94 64_107 9185.1 95 89.2 81.8 94 71_107 90.4 83.6 95 89.2 81.8 94 76_107 88.6 77.696 89.2 81.8 94 80_107 89.2 79.1 96 89.2 81.8 94 81_107 92.8 86.4 9789.2 81.8 94 84_107 89.2 80.6 95 89.2 81.8 94 86_107 90.4 79.1 98 89.281.8 94 93_107 89.8 79.1 97 89.2 81.8 94 11_108 90.4 77.6 99 89.2 81.894 29_108 91 80.6 98 89.2 81.8 94 38_108 86.2 71.6 96 89.2 81.8 9456_108 90.4 80.6 97 89.2 81.8 94 102_108 89.2 79.1 96 89.2 81.8 94 5_6391 86.6 94 89.2 81.8 94 6_54 90.4 83.6 95 89.2 81.8 94 6_55 86.8 74.6 9589.2 81.8 94 6_71 87.4 77.6 94 89.2 81.8 94 6_80 86.2 73.1 95 89.2 81.894 7_41 91.6 89.6 93 89.2 81.8 94 7_49 91 85.1 95 89.2 81.8 94 7_56 91.686.6 95 89.2 81.8 94 7_63 93.4 88.1 97 89.2 81.8 94 7_68 91.6 83.6 9789.2 81.8 94 9_30 87.4 82.1 91 89.2 81.8 94 13_38 86.2 82.1 89 89.2 81.894 13_112 85.6 83.6 87 89.2 81.8 94 13_71 88 82.1 92 89.2 81.8 94 13_9086.2 82.1 89 89.2 81.8 94 14_29 90.4 76.1 100 89.2 81.8 94 14_83 83.868.7 94 89.2 81.8 94 15_58 88 79.1 94 89.2 81.8 94 17_25 87.4 74.6 9689.2 81.8 94 17_90 84.4 71.6 93 89.2 81.8 94 18_39 84.4 71.6 93 89.281.8 94 18_60 88.6 77.6 96 89.2 81.8 94 18_62 86.8 76.1 94 89.2 81.8 9418_82 86.2 82.1 89 89.2 81.8 94 18_91 89.2 80.6 95 89.2 81.8 94 18_9484.4 77.6 89 89.2 81.8 94 18_104 83.2 73.1 90 89.2 81.8 94 19_79 85 76.191 89.2 81.8 94 24_61 83.2 71.6 91 89.2 81.8 94 25_30 88.6 77.6 96 89.281.8 94 35_38 83.2 70.1 92 89.2 81.8 94 37_42 84.4 74.6 91 89.2 81.8 9437_67 79.6 68.7 87 89.2 81.8 94 38_58 83.2 70.1 92 89.2 81.8 94 55_11280.8 65.7 91 89.2 81.8 94 46_60 85.6 74.6 93 89.2 81.8 94 51_97 89.282.1 94 89.2 81.8 94 83_113 85 76.1 91 89.2 81.8 94 4_106 89.2 77.6 9788 81.8 92 54_106 91.6 80.6 99 88 81.8 92 32_107 91 79.1 99 88 81.8 9242_107 86.8 74.6 95 88 81.8 92 63_107 92.2 85.1 97 88 81.8 92 78_107 8876.1 96 88 81.8 92 88_107 91 80.6 98 88 81.8 92 90_107 89.8 80.6 96 8881.8 92 3_70 94 88.1 98 88 81.8 92 3_75 92.8 89.6 95 88 81.8 92 4_7387.4 77.6 94 88 81.8 92 22_108 88 80.6 93 88 81.8 92 36_108 86.8 73.1 9688 81.8 92 40_108 89.8 79.1 97 88 81.8 92 5_6 95.2 94 96 88 81.8 92 5_4387.4 82.1 91 88 81.8 92 5_48 94 89.6 97 88 81.8 92 5_62 89.2 85.1 92 8881.8 92 5_64 89.8 82.1 95 88 81.8 92 5_65 88 79.1 94 88 81.8 92 5_11489.8 82.1 95 88 81.8 92 5_73 92.2 89.6 94 88 81.8 92 5_88 91 82.1 97 8881.8 92 6_96 88.6 83.6 92 88 81.8 92 7_40 95.2 89.6 99 88 81.8 92 7_6192.2 88.1 95 88 81.8 92 7_116 91 85.1 95 88 81.8 92 8_11 91.6 88.1 94 8881.8 92 37_110 88 83.6 91 88 81.8 92 9_17 83.8 73.1 91 88 81.8 92 9_3985 76.1 91 88 81.8 92 9_44 88 82.1 92 88 81.8 92 9_114 83.2 77.6 87 8881.8 92 9_87 82.6 80.6 84 88 81.8 92 10_49 91 89.6 92 88 81.8 92 10_6588 83.6 91 88 81.8 92 10_87 86.8 82.1 90 88 81.8 92 10_90 86.2 83.6 8888 81.8 92 11_38 85.6 76.1 92 88 81.8 92 13_37 90.4 89.6 91 88 81.8 9213_44 88 86.6 89 88 81.8 92 13_51 88.6 85.1 91 88 81.8 92 13_59 86.879.1 92 88 81.8 92 14_20 91 82.1 97 88 81.8 92 14_58 89.2 82.1 94 8881.8 92 18_36 88.6 82.1 93 88 81.8 92 19_25 83.8 70.1 93 88 81.8 9219_55 89.2 82.1 94 88 81.8 92 19_67 86.8 77.6 93 88 81.8 92 21_38 86.877.6 93 88 81.8 92 22_29 88 82.1 92 88 81.8 92 22_111 83.2 67.2 94 8881.8 92 25_62 80.8 74.6 85 88 81.8 92 29_55 83.2 74.6 89 88 81.8 9229_66 82.6 70.1 91 88 81.8 92 34_51 86.2 82.1 89 88 81.8 92 34_60 84.477.6 89 88 81.8 92 35_73 81.4 71.6 88 88 81.8 92 58_111 79 64.2 89 8881.8 92 37_112 84.4 74.6 91 88 81.8 92 51_112 86.8 80.6 91 88 81.8 9246_51 84.4 73.1 92 88 81.8 92 51_75 80.8 68.7 89 88 81.8 92 51_119 80.870.1 88 88 81.8 92 51_96 82 70.1 90 88 81.8 92 98_113 86.7 75.8 94 8881.8 92 90_94 75.4 56.7 88 88 81.8 92 72_108 89.2 79.1 96 87.8 81.8 91.839_106 89.8 79.1 97 86.7 81.8 90 44_106 91 80.6 98 86.7 81.8 90 47_10689.2 79.1 96 86.7 81.8 90 64_106 89.8 80.6 96 86.7 81.8 90 66_106 89.876.1 99 86.7 81.8 90 97_106 89.8 82.1 95 86.7 81.8 90 98_106 89.8 80.396 86.7 81.8 90 91_107 90.4 79.1 98 86.7 81.8 90 3_93 94.6 91 97 86.781.8 90 4_15 89.2 82.1 94 86.7 81.8 90 4_17 87.4 73.1 97 86.7 81.8 904_29 89.2 79.1 96 86.7 81.8 90 4_60 86.8 73.1 96 86.7 81.8 90 10_10886.2 74.6 94 86.7 81.8 90 16_108 90.4 86.6 93 86.7 81.8 90 28_108 87.480.6 92 86.7 81.8 90 51_108 86.8 74.6 95 86.7 81.8 90 67_108 88.6 79.195 86.7 81.8 90 69_108 86.8 77.6 93 86.7 81.8 90 82_108 86.8 76.1 9486.7 81.8 90 91_108 86.8 77.6 93 86.7 81.8 90 5_59 91 86.6 94 86.7 81.890 5_118 89.2 83.6 93 86.7 81.8 90 5_85 87.4 83.6 90 86.7 81.8 90 5_8692.8 89.6 95 86.7 81.8 90 6_34 89.2 82.1 94 86.7 81.8 90 6_35 88.6 76.197 86.7 81.8 90 6_66 88.6 76.1 97 86.7 81.8 90 15_109 86.2 73.1 95 86.781.8 90 9_26 89.2 86.6 91 86.7 81.8 90 9_54 86.8 82.1 90 86.7 81.8 909_66 83.8 77.6 88 86.7 81.8 90 9_80 84.4 80.6 87 86.7 81.8 90 9_97 87.485.1 89 86.7 81.8 90 10_46 90.4 80.6 97 86.7 81.8 90 10_56 83.8 74.6 9086.7 81.8 90 10_117 85 74.6 92 86.7 81.8 90 10_75 86.2 76.1 93 86.7 81.890 12_42 84.9 72.7 93 86.7 81.8 90 12_67 86.7 78.8 92 86.7 81.8 90 13_1486.2 79.1 91 86.7 81.8 90 13_65 86.8 83.6 89 86.7 81.8 90 17_21 85.673.1 94 86.7 81.8 90 17_24 83.8 73.1 91 86.7 81.8 90 17_31 85.6 70.1 9686.7 81.8 90 17_42 83.8 64.2 97 86.7 81.8 90 17_66 85.6 67.2 98 86.781.8 90 18_73 85 76.1 91 86.7 81.8 90 18_90 83.2 71.6 91 86.7 81.8 9021_62 78.4 62.7 89 86.7 81.8 90 22_26 86.2 77.6 92 86.7 81.8 90 22_3781.4 73.1 87 86.7 81.8 90 22_56 82 73.1 88 86.7 81.8 90 24_43 83.8 80.686 86.7 81.8 90 24_114 83.2 71.6 91 86.7 81.8 90 24_95 79.6 73.1 84 86.781.8 90 25_29 86.2 74.6 94 86.7 81.8 90 25_97 79.6 65.7 89 86.7 81.8 9026_31 86.8 76.1 94 86.7 81.8 90 26_35 86.2 77.6 92 86.7 81.8 90 27_11983.2 77.6 87 86.7 81.8 90 27_98 80.1 71.2 86 86.7 81.8 90 28_83 84.477.6 89 86.7 81.8 90 29_71 85.6 79.1 90 86.7 81.8 90 30_67 85.6 74.6 9386.7 81.8 90 35_101 77.8 67.2 85 86.7 81.8 90 66_111 83.2 64.2 96 86.781.8 90 39_42 83.2 70.1 92 86.7 81.8 90 39_51 86.2 77.6 92 86.7 81.8 9040_55 85.6 70.1 96 86.7 81.8 90 65_112 83.8 74.6 90 86.7 81.8 90 44_6780.2 71.6 86 86.7 81.8 90 47_66 78.4 65.7 87 86.7 81.8 90 61_67 79 67.287 86.7 81.8 90 66_118 80.8 65.7 91 86.7 81.8 90 67_120 75.4 61.2 8586.7 81.8 90 79_115 80.8 67.2 90 86.7 81.8 90 83_99 70.7 53.7 82 86.781.8 90 24_106 90.4 82.1 96 85.5 81.8 88 29_106 89.2 79.1 96 85.5 81.888 35_106 87.4 73.1 97 85.5 81.8 88 46_106 88.6 74.6 98 85.5 81.8 8858_106 90.4 79.1 98 85.5 81.8 88 80_106 88.6 76.1 97 85.5 81.8 88 82_10688.6 76.1 97 85.5 81.8 88 83_106 88.6 74.6 98 85.5 81.8 88 88_106 92.282.1 99 85.5 81.8 88 104_106 89.8 79.1 97 85.5 81.8 88 3_22 94 91 9685.5 81.8 88 3_31 95.2 91 98 85.5 81.8 88 3_79 94 91 96 85.5 81.8 884_111 85.6 71.6 95 85.5 81.8 88 32_108 88.6 82.1 93 85.5 81.8 88 78_10890.4 80.6 97 85.5 81.8 88 84_108 85.6 76.1 92 85.5 81.8 88 92_108 89.885.1 93 85.5 81.8 88 5_55 89.8 82.1 95 85.5 81.8 88 5_71 88 83.6 91 85.581.8 88 5_91 88.6 82.1 93 85.5 81.8 88 5_94 88.6 82.1 93 85.5 81.8 885_100 88 82.1 92 85.5 81.8 88 5_103 89.8 82.1 95 85.5 81.8 88 6_31 85.671.6 95 85.5 81.8 88 6_89 86.8 77.6 93 85.5 81.8 88 28_109 91 86.6 9485.5 81.8 88 38_109 85 73.1 93 85.5 81.8 88 9_110 89.2 82.1 94 85.5 81.888 9_42 85 79.1 89 85.5 81.8 88 9_47 82.6 77.6 86 85.5 81.8 88 9_62 80.274.6 84 85.5 81.8 88 9_74 86.8 80.6 91 85.5 81.8 88 10_24 88 82.1 9285.5 81.8 88 10_116 85.6 76.1 92 85.5 81.8 88 10_118 86.8 80.6 91 85.581.8 88 10_80 83.8 76.1 89 85.5 81.8 88 11_20 88 83.6 91 85.5 81.8 8811_56 82.6 73.1 89 85.5 81.8 88 11_62 83.8 71.6 92 85.5 81.8 88 11_11482.6 68.7 92 85.5 81.8 88 11_102 82 73.1 88 85.5 81.8 88 12_14 92.2 84.897 85.5 81.8 88 12_35 84.9 74.2 92 85.5 81.8 88 12_51 86.7 80.3 91 85.581.8 88 13_78 84.4 79.1 88 85.5 81.8 88 13_82 82.6 77.6 86 85.5 81.8 8813_94 85.6 82.1 88 85.5 81.8 88 13_100 83.2 80.6 85 85.5 81.8 88 16_4585 80.6 88 85.5 81.8 88 16_98 84.9 81.8 87 85.5 81.8 88 17_96 85 70.1 9585.5 81.8 88 18_83 82 73.1 88 85.5 81.8 88 20_21 83.2 74.6 89 85.5 81.888 20_42 83.8 71.6 92 85.5 81.8 88 21_30 85 79.1 89 85.5 81.8 88 21_4083.2 65.7 95 85.5 81.8 88 21_51 76 64.2 84 85.5 81.8 88 21_61 81.4 71.688 85.5 81.8 88 21_117 79 70.1 85 85.5 81.8 88 21_87 80.2 71.6 86 85.581.8 88 24_57 82.6 73.1 89 85.5 81.8 88 24_63 80.2 71.6 86 85.5 81.8 8825_82 83.2 74.6 89 85.5 81.8 88 27_58 79 70.1 85 85.5 81.8 88 31_47 78.467.2 86 85.5 81.8 88 35_36 80.2 67.2 89 85.5 81.8 88 35_56 80.2 67.2 8985.5 81.8 88 35_62 80.2 70.1 87 85.5 81.8 88 35_74 79 65.7 88 85.5 81.888 40_67 80.2 65.7 90 85.5 81.8 88 42_55 83.8 71.6 92 85.5 81.8 8842_120 79 68.7 86 85.5 81.8 88 42_98 81.3 63.6 93 85.5 81.8 88 75_11279.6 71.6 85 85.5 81.8 88 44_71 77.2 64.2 86 85.5 81.8 88 46_119 76 62.785 85.5 81.8 88 46_96 74.9 62.7 83 85.5 81.8 88 51_93 81.4 68.7 90 85.581.8 88 75_113 88 82.1 92 85.5 81.8 88 53_58 82.6 74.6 88 85.5 81.8 8866_80 78.4 58.2 92 85.5 81.8 88 66_120 77.8 61.2 89 85.5 81.8 88 45_10690.4 79.1 98 84.3 81.8 86 55_106 89.2 77.6 97 84.3 81.8 86 59_106 8874.6 97 84.3 81.8 86 63_106 89.8 80.6 96 84.3 81.8 86 67_106 88 74.6 9784.3 81.8 86 79_106 87.4 73.1 97 84.3 81.8 86 89_106 88 76.1 96 84.381.8 86 96_106 88 76.1 96 84.3 81.8 86 5_46 88 85.1 90 84.3 81.8 86 5_8187.3 83.3 90 84.3 81.8 86 5_120 88 85.1 90 84.3 81.8 86 5_121 88 85.1 9084.3 81.8 86 5_93 88 85.1 90 84.3 81.8 86 5_98 87.3 83.3 90 84.3 81.8 865_99 86.2 80.6 90 84.3 81.8 86 6_79 88.6 77.6 96 84.3 81.8 86 34_11086.2 86.6 86 84.3 81.8 86 9_65 83.8 79.1 87 84.3 81.8 86 9_67 82 76.1 8684.3 81.8 86 9_90 82.6 76.1 87 84.3 81.8 86 9_121 83.8 77.6 88 84.3 81.886 10_47 84.4 74.6 91 84.3 81.8 86 10_97 86.8 85.1 88 84.3 81.8 86 11_2285.6 76.1 92 84.3 81.8 86 11_44 83.8 79.1 87 84.3 81.8 86 11_65 86.277.6 92 84.3 81.8 86 11_80 80.8 67.2 90 84.3 81.8 86 11_81 79.5 69.7 8684.3 81.8 86 11_97 81.4 74.6 86 84.3 81.8 86 11_99 82.6 77.6 86 84.381.8 86 13_69 88 82.1 92 84.3 81.8 86 13_70 85.6 79.1 90 84.3 81.8 8616_93 83.2 77.6 87 84.3 81.8 86 17_56 82.6 62.7 96 84.3 81.8 86 18_6386.8 77.6 93 84.3 81.8 86 20_31 88 77.6 95 84.3 81.8 86 21_27 82 71.6 8984.3 81.8 86 21_53 82 76.1 86 84.3 81.8 86 21_116 80.2 70.1 87 84.3 81.886 22_28 81.4 76.1 85 84.3 81.8 86 22_42 82.6 68.7 92 84.3 81.8 86 22_4782.6 71.6 90 84.3 81.8 86 22_69 82 74.6 87 84.3 81.8 86 22_70 83.2 73.190 84.3 81.8 86 22_81 81.9 68.2 91 84.3 81.8 86 24_27 84.4 73.1 92 84.381.8 86 24_36 77.2 62.7 87 84.3 81.8 86 24_88 80.8 76.1 84 84.3 81.8 8625_114 83.2 70.1 92 84.3 81.8 86 25_78 82.6 70.1 91 84.3 81.8 86 25_8885 77.6 90 84.3 81.8 86 28_98 84.3 71.2 93 84.3 81.8 86 29_93 83.8 73.191 84.3 81.8 86 30_75 87.4 80.6 92 84.3 81.8 86 31_89 82.6 73.1 89 84.381.8 86 35_45 82.6 70.1 91 84.3 81.8 86 40_58 86.2 73.1 95 84.3 81.8 8642_83 78.4 62.7 89 84.3 81.8 86 42_96 78.4 62.7 89 84.3 81.8 86 56_11283.2 74.6 89 84.3 81.8 86 46_66 81.4 67.2 91 84.3 81.8 86 46_83 75.462.7 84 84.3 81.8 86 46_90 76.6 65.7 84 84.3 81.8 86 46_92 76 62.7 8584.3 81.8 86 46_99 73.1 62.7 80 84.3 81.8 86 58_100 73.7 59.7 83 84.381.8 86 65_66 80.8 70.1 88 84.3 81.8 86 65_94 78.4 65.7 87 84.3 81.8 8671_114 82 67.2 92 84.3 81.8 86 70_80 79.6 62.7 91 84.3 81.8 86 75_9877.1 63.6 86 84.3 81.8 86 13_72 87.4 85.1 89 84.1 81.8 85.7 92_106 89.279.1 96 83.1 81.8 84 94_106 88 76.1 96 83.1 81.8 84 3_52 90.4 85.1 9483.1 81.8 84 33_109 86.8 77.6 93 83.1 81.8 84 73_109 86.8 82.1 90 83.181.8 84 66_110 86.2 74.6 94 83.1 81.8 84 9_52 85 80.6 88 83.1 81.8 849_78 82.6 74.6 88 83.1 81.8 84 9_96 85 76.1 91 83.1 81.8 84 9_99 86.282.1 89 83.1 81.8 84 11_63 81.4 73.1 87 83.1 81.8 84 11_64 79.6 73.1 8483.1 81.8 84 11_93 79 70.1 85 83.1 81.8 84 11_96 80.2 70.1 87 83.1 81.884 11_104 83.2 70.1 92 83.1 81.8 84 13_75 86.8 85.1 88 83.1 81.8 8416_25 85 80.6 88 83.1 81.8 84 16_70 83.8 80.6 86 83.1 81.8 84 21_11285.6 79.1 90 83.1 81.8 84 21_47 85 76.1 91 83.1 81.8 84 21_91 80.8 71.687 83.1 81.8 84 21_101 79 70.1 85 83.1 81.8 84 22_82 80.8 70.1 88 83.181.8 84 25_84 82 73.1 88 83.1 81.8 84 29_47 82 70.1 90 83.1 81.8 8429_58 80.2 71.6 86 83.1 81.8 84 31_44 83.8 73.1 91 83.1 81.8 84 31_9978.4 67.2 86 83.1 81.8 84 34_70 82.6 77.6 86 83.1 81.8 84 35_88 76.667.2 83 83.1 81.8 84 35_95 79 65.7 88 83.1 81.8 84 42_46 82 70.1 90 83.181.8 84 42_99 79 58.2 93 83.1 81.8 84 46_114 82 71.6 89 83.1 81.8 8446_79 77.2 64.2 86 83.1 81.8 84 46_94 74.9 59.7 85 83.1 81.8 84 46_9875.9 62.1 85 83.1 81.8 84 55_66 76.6 64.2 85 83.1 81.8 84 55_82 80.865.7 91 83.1 81.8 84 65_119 77.2 68.7 83 83.1 81.8 84 65_80 80.2 71.6 8683.1 81.8 84 66_114 81.4 65.7 92 83.1 81.8 84 66_67 77.2 56.7 91 83.181.8 84 66_79 79 64.2 89 83.1 81.8 84 93_114 77.8 62.7 88 83.1 81.8 8467_119 79 62.7 90 83.1 81.8 84 79_85 74.9 58.2 86 83.1 81.8 84 99_104 7659.7 87 83.1 81.8 84 52_106 89.8 80.6 96 81.9 81.8 82 27_109 84.4 76.190 81.9 81.8 82 43_109 89.2 80.6 95 81.9 81.8 82 44_109 89.2 85.1 9281.9 81.8 82 45_109 87.4 82.1 91 81.9 81.8 82 63_109 86.2 82.1 89 81.981.8 82 31_110 88 79.1 94 81.9 81.8 82 9_16 82.6 79.1 85 81.9 81.8 829_63 84.4 79.1 88 81.9 81.8 82 9_92 82.6 76.1 87 81.9 81.8 82 10_45 92.288.1 95 81.9 81.8 82 11_67 80.2 70.1 87 81.9 81.8 82 11_118 82 79.1 8481.9 81.8 82 16_80 82.6 77.6 86 81.9 81.8 82 16_94 85.6 83.6 87 81.981.8 82 16_99 82 79.1 84 81.9 81.8 82 21_64 80.2 67.2 89 81.9 81.8 8221_114 79.6 68.7 87 81.9 81.8 82 22_79 81.4 71.6 88 81.9 81.8 82 25_6983.8 73.1 91 81.9 81.8 82 28_47 85 80.6 88 81.9 81.8 82 31_92 80.8 67.290 81.9 81.8 82 34_67 78.4 70.1 84 81.9 81.8 82 35_67 78.4 64.2 88 81.981.8 82 36_99 79 70.1 85 81.9 81.8 82 42_67 79.6 64.2 90 81.9 81.8 8242_79 80.8 62.7 93 81.9 81.8 82 42_93 81.4 65.7 92 81.9 81.8 82 46_58 7662.7 85 81.9 81.8 82 46_103 75.4 61.2 85 81.9 81.8 82 55_78 74.3 65.7 8081.9 81.8 82 66_87 73.7 59.7 83 81.9 81.8 82 67_83 72.5 58.2 82 81.981.8 82 75_115 79.6 67.2 88 81.9 81.8 82 57_109 85.6 76.1 92 80.7 81.880 97_109 85 82.1 87 80.7 81.8 80 11_69 81.4 71.6 88 80.7 81.8 80 21_6677.8 70.1 83 80.7 81.8 80 21_78 77.2 65.7 85 80.7 81.8 80 21_80 77.267.2 84 80.7 81.8 80 21_82 78.4 73.1 82 80.7 81.8 80 21_88 79 70.1 8580.7 81.8 80 21_103 77.8 68.7 84 80.7 81.8 80 21_104 76 68.7 81 80.781.8 80 28_93 80.8 76.1 84 80.7 81.8 80 31_52 85 73.1 93 80.7 81.8 8034_79 82 76.1 86 80.7 81.8 80 35_59 80.8 65.7 91 80.7 81.8 80 52_111 8271.6 89 80.7 81.8 80 66_69 83.8 70.1 93 80.7 81.8 80 65_109 86.2 79.1 9179.5 81.8 78 68_109 82.6 73.1 89 79.5 81.8 78 71_109 84.4 77.6 89 79.581.8 78 21_69 81.4 73.1 87 79.5 81.8 78 28_119 80.2 79.1 81 79.5 81.8 7867_97 74.9 59.7 85 79.5 81.8 78 71_78 73.1 61.2 81 79.5 81.8 78 11_10986.2 77.6 92 78.3 81.8 76 17_109 83.8 74.6 90 78.3 81.8 76 11_94 79.671.6 85 78.3 81.8 76 65_100 77.2 65.7 85 78.3 81.8 76 79_104 73.7 59.783 78.3 81.8 76 83_100 64.7 40.3 81 78.3 81.8 76 69_109 82.6 76.1 8777.1 81.8 74 78_109 84.4 77.6 89 77.1 81.8 74 84_109 84.4 74.6 91 77.181.8 74 93_109 82.6 74.6 88 77.1 81.8 74 31_65 81.4 76.1 85 77.1 81.8 74100_109 82 77.6 85 75.9 81.8 72 28_100 80.2 73.1 85 75.9 81.8 72 64_7977.8 67.2 85 75.9 81.8 72 70_100 75.4 59.7 86 75.9 81.8 72 10_100 86.280.6 90 74.7 81.8 70 67_69 79.6 71.6 85 74.7 81.8 70 13_50 85 79.1 8987.8 81.2 92 18_50 83.8 73.1 91 87.8 81.2 92 50_106 89.8 77.6 98 85.481.2 88 40_50 81.4 67.2 91 85.4 81.2 88 50_114 80.2 65.7 90 85.4 81.2 889_50 84.4 77.6 89 84.1 81.2 86 50_66 74.9 56.7 87 82.9 81.2 84 50_8174.1 57.6 85 82.9 81.2 84 11_50 77.8 68.7 84 81.7 81.2 82 50_58 76 59.787 81.7 81.2 82 50_83 70.7 52.2 83 81.7 81.2 82 23_109 83.2 71.6 91 75.681.2 72 6_77 89.2 80.6 95 91.4 80.6 98 77_107 90.4 85.1 94 88.9 80.6 9419_77 82.6 71.6 90 88.9 80.6 94 42_77 78.4 62.7 89 87.7 80.6 92 51_7780.2 62.7 92 87.7 80.6 92 6_28 91.6 85.1 96 91.6 78.8 100 6_43 86.2 76.193 91.6 78.8 100 6_87 90.4 82.1 96 91.6 78.8 100 7_15 91 82.1 97 91.678.8 100 8_15 89.8 85.1 93 91.6 78.8 100 10_41 86.8 74.6 95 91.6 78.8100 15_18 90.4 86.6 93 91.6 78.8 100 18_33 86.2 74.6 94 91.6 78.8 10014_106 91 79.1 99 90.4 78.8 98 41_106 91.6 82.1 98 90.4 78.8 98 2_86 9180.6 98 90.4 78.8 98 30_107 92.2 85.1 97 90.4 78.8 98 6_108 89.8 80.6 9690.4 78.8 98 15_108 88 76.1 96 90.4 78.8 98 30_108 92.8 85.1 98 90.478.8 98 41_108 91 82.1 97 90.4 78.8 98 68_108 87.4 76.1 95 90.4 78.8 986_14 91 80.6 98 90.4 78.8 98 7_110 91.6 82.1 98 90.4 78.8 98 9_19 8882.1 92 90.4 78.8 98 13_80 85 82.1 87 90.4 78.8 98 14_112 91.6 80.6 9990.4 78.8 98 15_39 89.2 79.1 96 90.4 78.8 98 18_32 89.2 80.6 95 90.478.8 98 18_118 85.6 76.1 92 90.4 78.8 98 24_41 82.6 68.7 92 90.4 78.8 9830_31 84.4 73.1 92 90.4 78.8 98 33_112 85.6 71.6 95 90.4 78.8 98 87_11183.2 67.2 94 90.4 78.8 98 7_106 92.2 82.1 99 89.2 78.8 96 28_106 93.485.1 99 89.2 78.8 96 61_106 91.6 80.6 99 89.2 78.8 96 19_107 94 88.1 9889.2 78.8 96 3_7 95.2 89.6 99 89.2 78.8 96 3_30 91 85.1 95 89.2 78.8 9617_108 87.4 71.6 98 89.2 78.8 96 5_8 95.2 91 98 89.2 78.8 96 5_122 90.485.1 94 89.2 78.8 96 6_22 85.6 74.6 93 89.2 78.8 96 6_90 87.4 80.6 9289.2 78.8 96 7_36 91.6 82.1 98 89.2 78.8 96 9_41 87.4 82.1 91 89.2 78.896 12_111 88 78.8 94 89.2 78.8 96 12_56 87.3 83.3 90 89.2 78.8 96 13_3689.8 83.6 94 89.2 78.8 96 13_41 85.6 85.1 86 89.2 78.8 96 14_34 89.882.1 95 89.2 78.8 96 14_37 89.8 79.1 97 89.2 78.8 96 14_44 89.8 76.1 9989.2 78.8 96 14_75 86.2 73.1 95 89.2 78.8 96 14_89 86.2 71.6 96 89.278.8 96 15_21 84.4 71.6 93 89.2 78.8 96 15_44 85 71.6 94 89.2 78.8 9618_112 84.4 76.1 90 89.2 78.8 96 18_44 85.6 74.6 93 89.2 78.8 96 18_11785 73.1 93 89.2 78.8 96 18_119 84.4 76.1 90 89.2 78.8 96 18_80 83.8 76.189 89.2 78.8 96 18_120 84.4 76.1 90 89.2 78.8 96 18_98 84.3 75.8 90 89.278.8 96 18_122 84.4 76.1 90 89.2 78.8 96 19_26 83.2 73.1 90 89.2 78.8 9619_31 87.4 76.1 95 89.2 78.8 96 19_52 86.8 80.6 91 89.2 78.8 96 20_33 8879.1 94 89.2 78.8 96 20_111 88.6 77.6 96 89.2 78.8 96 24_38 84.4 71.6 9389.2 78.8 96 25_38 85 67.2 97 89.2 78.8 96 30_112 85 79.1 89 89.2 78.896 30_94 82.6 73.1 89 89.2 78.8 96 33_71 82.6 73.1 89 89.2 78.8 96 33_9983.8 68.7 94 89.2 78.8 96 98_111 77.7 56.1 92 89.2 78.8 96 37_70 79 71.684 89.2 78.8 96 38_46 87.4 76.1 95 89.2 78.8 96 40_42 82.6 61.2 97 89.278.8 96 41_120 80.8 73.1 86 89.2 78.8 96 96_113 85 74.6 92 89.2 78.8 9636_106 91 79.1 99 88 78.8 94 37_106 91 80.6 98 88 78.8 94 60_106 91.682.1 98 88 78.8 94 62_106 91 80.6 98 88 78.8 94 74_106 91 80.6 98 8878.8 94 90_106 89.8 77.6 98 88 78.8 94 3_107 92.8 86.6 97 88 78.8 946_107 88 76.1 96 88 78.8 94 27_107 91 83.6 96 88 78.8 94 48_107 91 82.197 88 78.8 94 57_107 91 82.1 97 88 78.8 94 73_107 91 80.6 98 88 78.8 94102_107 90.4 79.1 98 88 78.8 94 3_37 91.6 88.1 94 88 78.8 94 27_108 90.479.1 98 88 78.8 94 33_108 86.8 73.1 96 88 78.8 94 57_108 87.4 71.6 98 8878.8 94 6_9 88.6 79.1 95 88 78.8 94 6_25 86.2 74.6 94 88 78.8 94 6_8586.2 79.1 91 88 78.8 94 6_98 86.7 77.3 93 88 78.8 94 7_60 92.8 89.6 9588 78.8 94 8_31 89.2 82.1 94 88 78.8 94 8_42 89.8 79.1 97 88 78.8 9426_110 91 86.6 94 88 78.8 94 9_38 83.2 76.1 88 88 78.8 94 10_19 88.679.1 95 88 78.8 94 10_43 88 83.6 91 88 78.8 94 12_13 92.2 89.4 94 8878.8 94 13_29 89.2 82.1 94 88 78.8 94 13_39 86.8 74.6 95 88 78.8 9414_52 89.2 79.1 96 88 78.8 94 15_119 85 77.6 90 88 78.8 94 17_54 87.471.6 98 88 78.8 94 17_64 85 68.7 96 88 78.8 94 17_120 84.4 68.7 95 8878.8 94 18_29 85 74.6 92 88 78.8 94 18_114 85 74.6 92 88 78.8 94 18_7180.2 70.1 87 88 78.8 94 18_86 86.2 77.6 92 88 78.8 94 18_92 84.4 76.1 9088 78.8 94 18_99 83.8 74.6 90 88 78.8 94 20_25 89.8 83.6 94 88 78.8 9424_49 83.8 79.1 87 88 78.8 94 24_116 82.6 67.2 93 88 78.8 94 24_87 82.668.7 92 88 78.8 94 30_39 89.8 82.1 95 88 78.8 94 30_70 85.6 74.6 93 8878.8 94 34_38 85 74.6 92 88 78.8 94 38_98 82.5 65.2 94 88 78.8 94 39_11387.4 76.1 95 88 78.8 94 39_60 88 74.6 97 88 78.8 94 40_46 85 74.6 92 8878.8 94 41_66 79.6 62.7 91 88 78.8 94 41_83 79 65.7 88 88 78.8 94 71_11279.6 65.7 89 88 78.8 94 83_112 77.2 64.2 86 88 78.8 94 46_62 80.2 70.187 88 78.8 94 58_73 80.8 71.6 87 88 78.8 94 59_119 82 64.2 94 88 78.8 9467_115 78.4 68.7 85 88 78.8 94 83_115 83.8 73.1 91 88 78.8 94 70_120 7659.7 87 88 78.8 94 72_107 89.2 79.1 96 87.8 78.8 93.9 22_106 89.2 79.196 86.7 78.8 92 32_106 91 77.6 100 86.7 78.8 92 33_106 90.4 80.6 97 86.778.8 92 11_107 89.8 80.6 96 86.7 78.8 92 3_98 90.4 86.4 93 86.7 78.8 925_61 89.8 86.6 92 86.7 78.8 92 5_70 87.4 80.6 92 86.7 78.8 92 5_101 87.480.6 92 86.7 78.8 92 6_83 85.6 76.1 92 86.7 78.8 92 41_109 89.2 83.6 9386.7 78.8 92 9_111 83.8 71.6 92 86.7 78.8 92 9_43 88.6 85.1 91 86.7 78.892 9_113 86.8 79.1 92 86.7 78.8 92 9_115 85 79.1 89 86.7 78.8 92 10_1487.4 76.1 95 86.7 78.8 92 10_21 89.8 82.1 95 86.7 78.8 92 10_33 85 73.193 86.7 78.8 92 11_28 86.8 76.1 94 86.7 78.8 92 11_113 86.8 77.6 93 86.778.8 92 13_58 85 76.1 91 86.7 78.8 92 13_68 87.4 79.1 93 86.7 78.8 9213_115 85.6 82.1 88 86.7 78.8 92 14_26 89.2 76.1 98 86.7 78.8 92 14_3184.4 70.1 94 86.7 78.8 92 14_119 88 76.1 96 86.7 78.8 92 15_42 85 68.796 86.7 78.8 92 17_22 85 71.6 94 86.7 78.8 92 17_46 84.4 71.6 93 86.778.8 92 17_55 88 74.6 97 86.7 78.8 92 17_58 85 73.1 93 86.7 78.8 9217_65 85 70.1 95 86.7 78.8 92 17_94 83.2 68.7 93 86.7 78.8 92 18_28 89.882.1 95 86.7 78.8 92 18_61 85.6 76.1 92 86.7 78.8 92 18_121 83.8 77.6 8886.7 78.8 92 19_81 86.1 80.3 90 86.7 78.8 92 22_113 87.4 80.6 92 86.778.8 92 24_113 83.2 73.1 90 86.7 78.8 92 25_40 86.2 73.1 95 86.7 78.8 9225_42 84.4 71.6 93 86.7 78.8 92 25_116 84.4 74.6 91 86.7 78.8 92 26_2985 74.6 92 86.7 78.8 92 29_70 82 71.6 89 86.7 78.8 92 30_119 80.2 74.684 86.7 78.8 92 33_55 83.2 67.2 94 86.7 78.8 92 36_119 80.8 71.6 87 86.778.8 92 55_111 81.4 67.2 91 86.7 78.8 92 37_66 79 68.7 86 86.7 78.8 9239_46 77.8 65.7 86 86.7 78.8 92 39_70 78.4 64.2 88 86.7 78.8 92 39_7577.8 65.7 86 86.7 78.8 92 40_112 86.8 74.6 95 86.7 78.8 92 41_67 80.264.2 91 86.7 78.8 92 91_112 82.6 65.7 94 86.7 78.8 92 93_112 77.8 65.786 86.7 78.8 92 46_55 79 64.2 89 86.7 78.8 92 66_113 83.8 68.7 94 86.778.8 92 79_113 84.4 73.1 92 86.7 78.8 92 52_53 84.4 79.1 88 86.7 78.8 9258_119 75.4 62.7 84 86.7 78.8 92 58_87 82 74.6 87 86.7 78.8 92 98_11581.9 65.2 93 86.7 78.8 92 15_106 89.8 77.6 98 85.5 78.8 90 65_106 93.486.6 98 85.5 78.8 90 81_106 91 80.3 98 85.5 78.8 90 85_106 88.6 79.1 9585.5 78.8 90 69_107 87.4 77.6 94 85.5 78.8 90 3_9 93.4 88.1 97 85.5 78.890 3_45 92.8 86.6 97 85.5 78.8 90 3_46 93.4 88.1 97 85.5 78.8 90 61_10891.6 86.6 95 85.5 78.8 90 73_108 86.2 73.1 95 85.5 78.8 90 5_58 86.877.6 93 85.5 78.8 90 5_69 90.4 83.6 95 85.5 78.8 90 5_76 90.4 83.6 9585.5 78.8 90 5_84 89.2 85.1 92 85.5 78.8 90 5_92 88.6 85.1 91 85.5 78.890 5_95 89.8 83.6 94 85.5 78.8 90 6_11 85.6 74.6 93 85.5 78.8 90 8_3589.2 82.1 94 85.5 78.8 90 8_40 87.4 76.1 95 85.5 78.8 90 9_10 86.8 82.190 85.5 78.8 90 9_32 84.4 79.1 88 85.5 78.8 90 9_48 84.4 80.6 87 85.578.8 90 10_25 82.6 73.1 89 85.5 78.8 90 10_70 88 77.6 95 85.5 78.8 9012_66 82.5 72.7 89 85.5 78.8 90 12_95 85.5 78.8 90 85.5 78.8 90 13_34 9185.1 95 85.5 78.8 90 13_52 89.2 82.1 94 85.5 78.8 90 13_99 84.4 80.6 8785.5 78.8 90 15_52 88 82.1 92 85.5 78.8 90 16_55 84.4 79.1 88 85.5 78.890 17_45 85.6 73.1 94 85.5 78.8 90 17_118 83.8 70.1 93 85.5 78.8 9017_83 83.2 67.2 94 85.5 78.8 90 17_85 83.8 67.2 95 85.5 78.8 90 17_88 8267.2 92 85.5 78.8 90 17_97 83.2 70.1 92 85.5 78.8 90 18_65 86.2 76.1 9385.5 78.8 90 21_32 84.4 80.6 87 85.5 78.8 90 21_73 79.6 76.1 82 85.578.8 90 22_40 87.4 76.1 95 85.5 78.8 90 22_57 86.8 79.1 92 85.5 78.8 9022_76 77.8 64.2 87 85.5 78.8 90 24_28 85 79.1 89 85.5 78.8 90 24_11183.8 73.1 91 85.5 78.8 90 24_47 77.8 65.7 86 85.5 78.8 90 24_62 82.668.7 92 85.5 78.8 90 25_43 85 76.1 91 85.5 78.8 90 25_51 83.2 71.6 9185.5 78.8 90 25_113 83.2 68.7 93 85.5 78.8 90 25_115 82.6 68.7 92 85.578.8 90 28_55 87.4 76.1 95 85.5 78.8 90 28_58 87.4 79.1 93 85.5 78.8 9029_119 83.8 80.6 86 85.5 78.8 90 34_115 82.6 73.1 89 85.5 78.8 90 99_11181.4 62.7 94 85.5 78.8 90 38_55 88 73.1 98 85.5 78.8 90 39_104 80.2 65.790 85.5 78.8 90 40_81 80.7 68.2 89 85.5 78.8 90 41_79 81.4 68.7 90 85.578.8 90 42_112 82 67.2 92 85.5 78.8 90 42_56 82 71.6 89 85.5 78.8 9068_112 82.6 70.1 91 85.5 78.8 90 45_66 79 68.7 86 85.5 78.8 90 51_8177.7 66.7 85 85.5 78.8 90 51_98 80.7 72.7 86 85.5 78.8 90 94_113 84.470.1 94 85.5 78.8 90 58_117 78.4 61.2 90 85.5 78.8 90 58_80 78.4 62.7 8985.5 78.8 90 58_99 76.6 61.2 87 85.5 78.8 90 62_66 79 64.2 89 85.5 78.890 99_114 79 67.2 87 85.5 78.8 90 81_115 78.3 66.7 86 85.5 78.8 90 76_9880.7 69.7 88 85.5 78.8 90 27_106 89.2 76.1 98 84.3 78.8 88 68_106 89.879.1 97 84.3 78.8 88 75_106 88 74.6 97 84.3 78.8 88 84_106 89.2 79.1 9684.3 78.8 88 91_106 89.8 79.1 97 84.3 78.8 88 3_111 88.6 79.1 95 84.378.8 88 3_103 91.6 86.6 95 84.3 78.8 88 4_110 91 86.6 94 84.3 78.8 8895_108 89.8 85.1 93 84.3 78.8 88 104_108 88 79.1 94 84.3 78.8 88 5_11095.2 91 98 84.3 78.8 88 5_27 88.6 83.6 92 84.3 78.8 88 6_39 89.8 85.1 9384.3 78.8 88 6_45 90.4 80.6 97 84.3 78.8 88 6_67 87.4 74.6 96 84.3 78.888 6_93 87.4 76.1 95 84.3 78.8 88 9_59 86.8 79.1 92 84.3 78.8 88 9_8685.6 80.6 89 84.3 78.8 88 9_88 83.8 79.1 87 84.3 78.8 88 9_103 82.6 74.688 84.3 78.8 88 9_104 81.4 76.1 85 84.3 78.8 88 10_60 83.8 71.6 92 84.378.8 88 11_47 83.8 74.6 90 84.3 78.8 88 11_76 82 71.6 89 84.3 78.8 8811_120 79.6 68.7 87 84.3 78.8 88 12_16 88 89.4 87 84.3 78.8 88 12_3187.3 80.3 92 84.3 78.8 88 12_78 85.5 80.3 89 84.3 78.8 88 13_62 83.282.1 84 84.3 78.8 88 13_93 83.8 82.1 85 84.3 78.8 88 14_100 85.6 71.6 9584.3 78.8 88 16_34 88 85.1 90 84.3 78.8 88 16_39 89.2 86.6 91 84.3 78.888 16_97 84.4 85.1 84 84.3 78.8 88 17_27 85 70.1 95 84.3 78.8 88 17_3984.4 74.6 91 84.3 78.8 88 17_44 85 70.1 95 84.3 78.8 88 17_121 83.2 67.294 84.3 78.8 88 22_74 83.2 77.6 87 84.3 78.8 88 24_84 79.6 68.7 87 84.378.8 88 25_32 84.4 73.1 92 84.3 78.8 88 25_74 83.8 74.6 90 84.3 78.8 8825_76 80.8 67.2 90 84.3 78.8 88 25_91 81.4 67.2 91 84.3 78.8 88 27_2883.2 74.6 89 84.3 78.8 88 28_94 82 73.1 88 84.3 78.8 88 28_96 86.2 76.193 84.3 78.8 88 29_42 80.2 64.2 91 84.3 78.8 88 29_96 78.4 70.1 84 84.378.8 88 31_115 80.8 67.2 90 84.3 78.8 88 32_46 85 77.6 90 84.3 78.8 8832_55 86.8 82.1 90 84.3 78.8 88 35_111 82 65.7 93 84.3 78.8 88 35_6878.4 64.2 88 84.3 78.8 88 37_100 79 67.2 87 84.3 78.8 88 39_44 80.2 67.289 84.3 78.8 88 40_66 81.4 61.2 95 84.3 78.8 88 42_66 80.2 59.7 94 84.378.8 88 76_112 88 80.6 93 84.3 78.8 88 78_112 77.2 61.2 88 84.3 78.8 8881_112 77.7 62.1 88 84.3 78.8 88 44_78 79.6 68.7 87 84.3 78.8 88 46_7575.4 67.2 81 84.3 78.8 88 46_85 76.6 61.2 87 84.3 78.8 88 46_93 74.959.7 85 84.3 78.8 88 51_55 79 67.2 87 84.3 78.8 88 53_67 77.2 67.2 8484.3 78.8 88 53_75 81.4 70.1 89 84.3 78.8 88 53_83 76.6 62.7 86 84.378.8 88 55_62 83.8 70.1 93 84.3 78.8 88 56_58 79 64.2 89 84.3 78.8 8856_114 79 70.1 85 84.3 78.8 88 56_119 77.8 65.7 86 84.3 78.8 88 62_7080.2 64.2 91 84.3 78.8 88 65_70 83.2 70.1 92 84.3 78.8 88 65_98 76.562.1 86 84.3 78.8 88 66_71 80.2 67.2 89 84.3 78.8 88 66_74 80.8 67.2 9084.3 78.8 88 66_81 77.7 62.1 88 84.3 78.8 88 66_89 80.2 68.7 88 84.378.8 88 75_114 81.4 70.1 89 84.3 78.8 88 71_104 80.8 65.7 91 84.3 78.888 81_89 77.1 62.1 87 84.3 78.8 88 90_98 74.1 57.6 85 84.3 78.8 8872_106 89.2 79.1 96 84.1 78.8 87.8 9_72 85 79.1 89 84.1 78.8 87.8 18_7287.4 80.6 92 84.1 78.8 87.8 6_106 89.8 79.1 97 83.1 78.8 86 10_106 8876.1 96 83.1 78.8 86 11_106 89.2 77.6 97 83.1 78.8 86 42_106 89.2 77.697 83.1 78.8 86 57_106 89.2 76.1 98 83.1 78.8 86 69_106 89.2 77.6 9783.1 78.8 86 76_106 89.2 77.6 97 83.1 78.8 86 3_56 91.6 85.1 96 83.178.8 86 5_67 87.4 82.1 91 83.1 78.8 86 6_121 86.8 76.1 94 83.1 78.8 8646_110 83.8 77.6 88 83.1 78.8 86 9_28 86.2 86.6 86 83.1 78.8 86 9_6482.6 74.6 88 83.1 78.8 86 9_76 83.8 77.6 88 83.1 78.8 86 9_79 85.6 79.190 83.1 78.8 86 9_82 84.4 79.1 88 83.1 78.8 86 9_95 86.8 80.6 91 83.178.8 86 9_101 85.6 83.6 87 83.1 78.8 86 10_11 85.6 74.6 93 83.1 78.8 8610_111 82 68.7 91 83.1 78.8 86 10_40 85.6 74.6 93 83.1 78.8 86 11_5980.8 73.1 86 83.1 78.8 86 11_68 79 71.6 84 83.1 78.8 86 11_117 80.2 70.187 83.1 78.8 86 11_74 81.4 74.6 86 83.1 78.8 86 11_90 79.6 73.1 84 83.178.8 86 13_55 90.4 83.6 95 83.1 78.8 86 16_44 82.6 76.1 87 83.1 78.8 8616_65 82.6 80.6 84 83.1 78.8 86 16_66 80.8 73.1 86 83.1 78.8 86 16_7183.8 77.6 88 83.1 78.8 86 17_52 84.4 71.6 93 83.1 78.8 86 17_98 84.368.2 95 83.1 78.8 86 21_76 79 73.1 83 83.1 78.8 86 22_31 80.2 68.7 8883.1 78.8 86 22_43 86.2 76.1 93 83.1 78.8 86 22_90 79.6 70.1 86 83.178.8 86 22_91 77.8 67.2 85 83.1 78.8 86 26_67 83.2 74.6 89 83.1 78.8 8628_34 88.6 79.1 95 83.1 78.8 86 28_52 87.4 80.6 92 83.1 78.8 86 29_11180.2 65.7 90 83.1 78.8 86 29_112 83.8 73.1 91 83.1 78.8 86 29_45 85 79.189 83.1 78.8 86 29_46 81.4 73.1 87 83.1 78.8 86 31_40 82 67.2 92 83.178.8 86 31_46 77.8 65.7 86 83.1 78.8 86 32_66 82.6 71.6 90 83.1 78.8 8632_98 86.1 80.3 90 83.1 78.8 86 34_66 83.2 74.6 89 83.1 78.8 86 35_11677.2 59.7 89 83.1 78.8 86 39_66 78.4 64.2 88 83.1 78.8 86 42_71 81.465.7 92 83.1 78.8 86 42_81 84.3 72.7 92 83.1 78.8 86 44_83 76.6 61.2 8783.1 78.8 86 44_93 77.8 67.2 85 83.1 78.8 86 46_120 73.7 59.7 83 83.178.8 86 51_65 82 74.6 87 83.1 78.8 86 51_66 79.6 64.2 90 83.1 78.8 8651_94 80.2 67.2 89 83.1 78.8 86 54_56 85.6 83.6 87 83.1 78.8 86 55_7577.8 62.7 88 83.1 78.8 86 55_94 75.4 59.7 86 83.1 78.8 86 55_98 73.556.1 85 83.1 78.8 86 58_82 77.2 59.7 89 83.1 78.8 86 58_93 74.9 58.2 8683.1 78.8 86 62_81 70.5 57.6 79 83.1 78.8 86 64_67 82.6 73.1 89 83.178.8 86 66_96 77.2 61.2 88 83.1 78.8 86 67_98 76.5 60.6 87 83.1 78.8 8617_106 89.8 79.1 97 81.9 78.8 84 70_106 88.6 74.6 98 81.9 78.8 84 64_10986.2 80.6 90 81.9 78.8 84 39_110 87.4 83.6 90 81.9 78.8 84 9_31 83.876.1 89 81.9 78.8 84 9_81 85.5 80.3 89 81.9 78.8 84 10_31 85.6 79.1 9081.9 78.8 84 10_63 83.8 79.1 87 81.9 78.8 84 10_114 87.4 77.6 94 81.978.8 84 10_67 84.4 76.1 90 81.9 78.8 84 10_88 88.6 79.1 95 81.9 78.8 8411_36 79.6 70.1 86 81.9 78.8 84 11_57 79 68.7 86 81.9 78.8 84 11_58 80.871.6 87 81.9 78.8 84 11_82 80.8 68.7 89 81.9 78.8 84 11_89 80.2 70.1 8781.9 78.8 84 11_91 79.6 68.7 87 81.9 78.8 84 12_22 90.4 84.8 94 81.978.8 84 16_22 82 76.1 86 81.9 78.8 84 16_96 80.8 73.1 86 81.9 78.8 8417_75 83.8 67.2 95 81.9 78.8 84 17_100 83.2 71.6 91 81.9 78.8 84 22_5484.4 77.6 89 81.9 78.8 84 27_29 83.8 74.6 90 81.9 78.8 84 28_66 83.276.1 88 81.9 78.8 84 28_70 83.8 74.6 90 81.9 78.8 84 28_120 85 76.1 9181.9 78.8 84 29_34 81.4 74.6 86 81.9 78.8 84 31_32 86.2 79.1 91 81.978.8 84 31_66 76 64.2 84 81.9 78.8 84 31_85 77.2 67.2 84 81.9 78.8 8431_87 79 71.6 84 81.9 78.8 84 31_94 79 65.7 88 81.9 78.8 84 31_96 80.271.6 86 81.9 78.8 84 34_82 79 74.6 82 81.9 78.8 84 44_99 76 58.2 88 81.978.8 84 44_103 81.4 64.2 93 81.9 78.8 84 45_46 77.2 67.2 84 81.9 78.8 8446_82 73.7 61.2 82 81.9 78.8 84 47_51 80.2 67.2 89 81.9 78.8 84 47_12076.6 68.7 82 81.9 78.8 84 51_71 82.6 73.1 89 81.9 78.8 84 55_117 78.459.7 91 81.9 78.8 84 55_99 77.8 65.7 86 81.9 78.8 84 58_75 76 64.2 8481.9 78.8 84 58_94 76.6 58.2 89 81.9 78.8 84 83_114 82.6 65.7 94 81.978.8 84 94_114 78.4 64.2 88 81.9 78.8 84 67_118 73.7 52.2 88 81.9 78.884 67_121 75.4 64.2 83 81.9 78.8 84 78_119 73.1 56.7 84 81.9 78.8 8481_98 74.5 60 84 81.9 78.8 84 93_98 74.1 56.1 86 81.9 78.8 84 78_10689.2 77.6 97 80.7 78.8 82 100_106 89.2 80.6 95 80.7 78.8 82 10_109 86.277.6 92 80.7 78.8 82 74_109 89.2 82.1 94 80.7 78.8 82 102_109 84.4 73.192 80.7 78.8 82 79_110 86.8 76.1 94 80.7 78.8 82 96_110 86.2 85.1 8780.7 78.8 82 9_69 82.6 80.6 84 80.7 78.8 82 9_84 82 77.6 85 80.7 78.8 829_93 82.6 74.6 88 80.7 78.8 82 10_78 85.6 77.6 91 80.7 78.8 82 10_9383.8 77.6 88 80.7 78.8 82 10_103 85 77.6 90 80.7 78.8 82 11_42 83.2 76.188 80.7 78.8 82 11_95 78.4 68.7 85 80.7 78.8 82 11_100 78.4 68.7 85 80.778.8 82 24_78 79 64.2 89 80.7 78.8 82 25_28 82 74.6 87 80.7 78.8 8225_63 83.8 76.1 89 80.7 78.8 82 28_42 82 70.1 90 80.7 78.8 82 29_56 80.270.1 87 80.7 78.8 82 31_111 81.4 65.7 92 80.7 78.8 82 32_79 81.4 73.1 8780.7 78.8 82 92_111 77.2 62.7 87 80.7 78.8 82 39_100 74.9 61.2 84 80.778.8 82 42_57 79 58.2 93 80.7 78.8 82 42_121 81.4 70.1 89 80.7 78.8 8244_100 76 61.2 86 80.7 78.8 82 100_113 84.4 74.6 91 80.7 78.8 82 55_11882 67.2 92 80.7 78.8 82 55_81 76.5 54.5 91 80.7 78.8 82 55_87 77.2 65.785 80.7 78.8 82 62_93 77.2 65.7 85 80.7 78.8 82 78_114 77.2 65.7 85 80.778.8 82 70_96 74.3 62.7 82 80.7 78.8 82 70_103 80.2 65.7 90 80.7 78.8 8278_80 74.9 59.7 85 80.7 78.8 82 46_72 79 71.6 84 80.5 78.8 81.6 101_10986.8 79.1 92 79.5 78.8 80 10_95 82.6 74.6 88 79.5 78.8 80 16_78 82 76.186 79.5 78.8 80 21_29 82 73.1 88 79.5 78.8 80 21_95 81.4 67.2 91 79.578.8 80 27_45 83.2 80.6 85 79.5 78.8 80 28_45 89.2 86.6 91 79.5 78.8 8031_114 81.4 68.7 90 79.5 78.8 80 31_80 79.6 62.7 91 79.5 78.8 80 31_8879.6 71.6 85 79.5 78.8 80 31_97 82 73.1 88 79.5 78.8 80 42_100 77.8 56.792 79.5 78.8 80 45_79 78.4 67.2 86 79.5 78.8 80 46_121 75.4 61.2 85 79.578.8 80 46_100 74.9 64.2 82 79.5 78.8 80 55_100 76.6 59.7 88 79.5 78.880 56_98 74.7 60.6 84 79.5 78.8 80 58_78 76 62.7 85 79.5 78.8 80 65_7979 62.7 90 79.5 78.8 80 65_104 77.8 67.2 85 79.5 78.8 80 67_99 74.9 58.286 79.5 78.8 80 78_81 72.3 59.1 81 79.5 78.8 80 78_90 74.3 61.2 83 79.578.8 80 79_96 76 62.7 85 79.5 78.8 80 80_121 74.9 62.7 83 79.5 78.8 8094_99 71.9 53.7 84 79.5 78.8 80 3_92 92.8 89.6 95 78.3 78.8 78 6_10986.2 77.6 92 78.3 78.8 78 52_110 85.6 85.1 86 78.3 78.8 78 10_42 84.476.1 90 78.3 78.8 78 29_67 82.6 73.1 89 78.3 78.8 78 31_83 78.4 64.2 8878.3 78.8 78 46_52 79 70.1 85 78.3 78.8 78 67_79 74.9 56.7 87 78.3 78.878 67_93 73.1 53.7 86 78.3 78.8 78 67_103 76 58.2 88 78.3 78.8 78 70_9275.4 62.7 84 78.3 78.8 78 59_109 83.8 74.6 90 77.1 78.8 76 70_109 83.274.6 89 77.1 78.8 76 76_109 82.6 73.1 89 77.1 78.8 76 95_109 86.2 79.191 77.1 78.8 76 31_42 81.4 67.2 91 77.1 78.8 76 31_55 83.2 70.1 92 77.178.8 76 34_55 80.2 73.1 85 77.1 78.8 76 42_78 76 59.7 87 77.1 78.8 7667_85 71.3 56.7 81 77.1 78.8 76 78_85 72.5 55.2 84 77.1 78.8 76 79_9272.5 52.2 86 77.1 78.8 76 94_103 73.7 50.7 89 77.1 78.8 76 99_100 71.952.2 85 77.1 78.8 76 36_109 83.8 74.6 90 75.9 78.8 74 91_109 84.4 76.190 75.9 78.8 74 46_78 76 62.7 85 75.9 78.8 74 52_67 76 65.7 83 75.9 78.874 63_78 78.4 74.6 81 75.9 78.8 74 67_70 77.8 61.2 89 75.9 78.8 74 69_7980.2 71.6 86 75.9 78.8 74 31_104 77.8 65.7 86 74.7 78.8 72 63_79 79 68.786 74.7 78.8 72 67_92 73.1 56.7 84 74.7 78.8 72 75_78 76.6 65.7 84 74.778.8 72 69_78 74.9 61.2 84 73.5 78.8 70 79_100 74.3 59.7 84 73.5 78.8 7013_23 91 82.1 97 90.2 78.1 98 23_108 89.2 80.6 95 87.8 78.1 94 8_23 88.679.1 95 87.8 78.1 94 41_50 81.4 67.2 91 86.6 78.1 92 50_51 79 64.2 8985.4 78.1 90 50_87 78.4 62.7 89 85.4 78.1 90 37_50 82.6 71.6 90 84.178.1 88 9_23 87.4 82.1 91 82.9 78.1 86 50_68 79.6 64.2 90 82.9 78.1 8623_106 89.2 76.1 98 81.7 78.1 84 46_50 76.6 67.2 83 81.7 78.1 84 50_7576 64.2 84 81.7 78.1 84 50_111 79 61.2 91 80.5 78.1 82 31_50 82.6 70.191 78 78.1 78 50_78 73.7 62.7 81 74.4 78.1 72 77_110 84.4 76.1 90 88.977.4 96 18_77 83.2 74.6 89 86.4 77.4 92 77_115 79 67.2 87 86.4 77.4 9216_77 85.6 82.1 88 85.2 77.4 90 29_77 83.2 76.1 88 85.2 77.4 90 58_7774.3 56.7 86 85.2 77.4 90 66_77 76.6 59.7 88 85.2 77.4 90 77_104 79.662.7 91 84 77.4 88 11_77 80.2 71.6 86 82.7 77.4 86

Example 3

<Selection of Gene Markers Using all Samples and Method for EvaluatingPancreatic Cancer Discriminant Performance of Acquired Gene Markers>

In this Example, the samples of the training cohort and the validationcohort used in Examples 1 and 2 were integrated, and selection of a genemarker and evaluation of its pancreatic cancer discriminant performancewere conducted using all of the samples.

Specifically, the miRNA expression levels in the sera of the 100pancreatic cancer patients and the 150 healthy subjects obtained in thepreceding Reference Examples were normalized by quantile normalization.In order to acquire diagnosis markers with higher reliability, onlygenes having a gene expression level of 2⁶ or higher in 50% or more ofthe samples in either of the pancreatic cancer patient group or thehealthy subject group were selected in the gene marker selection. Inorder to further acquire statistical significance for discriminating apancreatic cancer patient group from a healthy subject group, the Pvalue obtained by two-tailed t-test assuming equal variance as to eachgene expression level was corrected by the Bonferroni method, and genesthat satisfied p<0.01 were selected as gene markers for use inexplanatory variables of a discriminant and described in Table 7. Inthis way, hsa-miR-4417, hsa-miR-4707-5p, hsa-miR-7847-3p, hsa-miR-2861,hsa-miR-4513, hsa-miR-7111-5p, hsa-miR-6777-5p, hsa-miR-7113-3p,hsa-miR-4648, hsa-miR-3184-5p, hsa-miR-4271, hsa-miR-6791-5p,hsa-miR-642a-3p, hsa-miR-7108-5p, hsa-miR-128-1-5p, hsa-miR-5196-5p,hsa-miR-3178, hsa-miR-3656, hsa-miR-92a-2-5p, hsa-miR-6769b-5p,hsa-miR-4689, hsa-miR-6076, hsa-miR-92b-5p, hsa-miR-6774-5p,hsa-miR-486-3p, hsa-miR-6806-5p, hsa-miR-6842-5p, hsa-miR-6716-5p,hsa-miR-557, hsa-miR-4673, hsa-miR-4674, hsa-miR-4442, hsa-miR-1915-3p,hsa-miR-4687-3p, and hsa-miR-92b-3p genes, and the nucleotide sequencesof SEQ ID NOs: 349 to 383 related thereto were found in addition to thegenes described in Table 2. As with the nucleotide sequences of SEQ IDNOs: 1 to 122, the results obtained about the polynucleotides shown inSEQ ID NOs: 349 to 383 also showed that the measurement values weresignificantly lower (−) or higher (+) in the pancreatic cancer patientgroup than in the healthy subject group (Table 7). These results wereable to be validated in the validation cohort. Thus, the presence orabsence of pancreatic cancer in the newly obtained samples can bedetermined by the methods described in Examples 1 and 2 by using, aloneor in combination, the gene expression level measurement valuesdescribed in Table 7.

TABLE 7 Expression level in pancreatic cancer patient relative to SEQ IDNO: Name p. value healthy subject 105 hsa-miR-125a-3p 7.05E−72 − 1hsa-miR-6893-5p 4.14E−64 − 2 hsa-miR-6075 1.06E−49 + 4 hsa-miR-42945.56E−43 − 107 hsa-miR-1469 1.06E−42 + 106 hsa-miR-204-3p 6.17E−42 − 108hsa-miR-575 1.26E−39 − 5 hsa-miR-6729-5p 1.24E−38 + 6 hsa-miR-44762.46E−36 − 3 hsa-miR-6820-5p 1.80E−34 − 8 hsa-miR-6765-3p 3.08E−32 − 109hsa-miR-150-3p 7.57E−31 − 7 hsa-miR-6836-3p 1.12E−29 + 18 hsa-miR-47924.50E−29 + 9 hsa-miR-6799-5p 3.91E−28 − 10 hsa-miR-4530 6.27E−27 − 13hsa-miR-615-5p 2.79E−26 − 12 hsa-miR-4454 4.13E−26 − 17 hsa-miR-44506.27E−26 − 11 hsa-miR-7641 1.99E−25 − 110 hsa-miR-423-5p 3.69E−25 − 24hsa-miR-6877-5p 4.17E−25 − 19 hsa-miR-665 6.54E−25 + 14 hsa-miR-80733.32E−24 + 35 hsa-miR-1231 4.73E−23 + 25 hsa-miR-6880-5p 4.77E−23 − 22hsa-miR-6789-5p 1.52E−22 + 16 hsa-miR-4634 3.85E−22 + 30 hsa-miR-5585-3p8.16E−22 + 20 hsa-miR-7975 1.73E−20 − 33 hsa-miR-4651 3.57E−19 − 31hsa-miR-6085 3.92E−19 − 26 hsa-miR-7977 4.07E−19 − 29 hsa-miR-80892.29E−18 − 112 hsa-miR-3188 3.55E−18 + 34 hsa-miR-4433-3p 6.97E−18 + 27hsa-miR-4734 8.43E−18 + 111 hsa-miR-564 8.77E−18 − 46 hsa-miR-61254.60E−17 + 21 hsa-miR-7109-5p 4.84E−17 − 23 hsa-miR-4497 1.63E−16 − 41hsa-miR-619-5p 2.74E−16 + 37 hsa-miR-7114-5p 2.89E−16 − 42hsa-miR-3622a-5p 4.11E−16 − 39 hsa-miR-8069 1.67E−15 + 58 hsa-miR-31852.47E−15 + 66 hsa-miR-4723-5p 2.57E−15 − 38 hsa-miR-1238-5p 2.84E−15 +44 hsa-miR-6741-5p 3.06E−15 − 40 hsa-miR-4732-5p 4.29E−15 + 32hsa-miR-6845-5p 1.09E−14 + 55 hsa-miR-6724-5p 1.51E−14 + 28hsa-miR-6821-5p 2.47E−14 − 50 hsa-miR-6875-5p 7.80E−14 + 113hsa-miR-1246 1.34E−13 + 53 hsa-miR-4736 2.22E−13 + 47 hsa-miR-6805-5p2.32E−13 + 36 hsa-miR-4665-5p 5.61E−13 − 114 hsa-miR-602 7.01E−13 + 45hsa-miR-6781-5p 1.70E−12 + 15 hsa-miR-663a 1.70E−12 + 57 hsa-miR-6726-5p2.61E−12 − 67 hsa-miR-6850-5p 4.31E−12 + 56 hsa-miR-7107-5p 7.43E−12 −52 hsa-miR-4433b-3p 7.79E−12 + 71 hsa-miR-4486 8.29E−12 + 65hsa-miR-6779-5p 1.76E−11 − 115 hsa-miR-1290 1.99E−11 + 51hsa-miR-1908-3p 2.20E−11 + 70 hsa-miR-8072 2.98E−11 + 60hsa-miR-1273g-3p 6.69E−11 + 43 hsa-miR-1260a 1.14E−10 − 79 hsa-miR-45342.20E−10 − 80 hsa-miR-4449 2.54E−10 + 77 hsa-miR-6780b-5p 2.77E−10 + 49hsa-miR-6872-3p 3.55E−10 − 119 hsa-miR-187-5p 3.74E−10 − 75hsa-miR-7106-5p 4.23E−10 − 54 hsa-miR-5100 5.83E−10 − 83 hsa-miR-44676.44E−10 + 59 hsa-miR-4638-5p 9.61E−10 − 81 hsa-miR-5195-3p 1.12E−09 −62 hsa-miR-328-5p 1.36E−09 − 68 hsa-miR-760 2.30E−09 − 78 hsa-miR-60902.36E−09 + 90 hsa-miR-3162-5p 3.27E−09 − 48 hsa-miR-6132 4.46E−09 − 120hsa-miR-1908-5p 4.47E−09 + 61 hsa-miR-6778-5p 6.12E−09 + 98hsa-miR-6816-5p 9.29E−09 + 94 hsa-miR-6722-3p 9.46E−09 + 82 hsa-miR-12021.14E−08 − 117 hsa-miR-451a 2.71E−08 − 118 hsa-miR-24-3p 3.63E−08 − 74hsa-miR-1260b 6.21E−08 − 73 hsa-miR-4656 6.81E−08 + 85 hsa-miR-42816.81E−08 − 99 hsa-miR-4741 9.33E−08 + 116 hsa-miR-16-5p 9.82E−08 − 121hsa-miR-371a-5p 1.38E−07 − 93 hsa-miR-1227-5p 1.43E−07 + 63hsa-miR-3679-3p 1.83E−07 + 72 hsa-miR-1913 3.84E−07 + 69 hsa-miR-77041.35E−06 − 87 hsa-miR-4484 1.46E−06 + 89 hsa-miR-3135b 1.72E−06 − 103hsa-miR-4665-3p 3.01E−06 + 349 hsa-miR-4417 3.10E−06 + 350hsa-miR-4707-5p 3.58E−06 + 88 hsa-miR-6805-3p 4.95E−06 + 351hsa-miR-7847-3p 5.06E−06 − 352 hsa-miR-2861 6.22E−06 − 104 hsa-miR-7187.23E−06 + 353 hsa-miR-4513 7.71E−06 − 76 hsa-miR-6889-5p 1.88E−05 − 92hsa-miR-6721-5p 2.26E−05 + 354 hsa-miR-7111-5p 2.67E−05 − 355hsa-miR-6777-5p 3.00E−05 − 91 hsa-miR-6768-5p 3.39E−05 − 356hsa-miR-7113-3p 3.47E−05 + 97 hsa-miR-6727-5p 3.73E−05 − 357hsa-miR-4648 4.03E−05 + 100 hsa-miR-4508 4.48E−05 + 358 hsa-miR-3184-5p4.67E−05 + 359 hsa-miR-4271 4.87E−05 − 96 hsa-miR-4746-3p 4.91E−05 + 360hsa-miR-6791-5p 7.71E−05 + 361 hsa-miR-642a-3p 2.26E−04 − 362hsa-miR-7108-5p 2.56E−04 + 363 hsa-miR-128-1-5p 2.70E−04 + 364hsa-miR-5196-5p 2.85E−04 − 365 hsa-miR-3178 6.64E−04 + 366 hsa-miR-36567.51E−04 + 367 hsa-miR-92a-2-5p 1.04E−03 − 368 hsa-miR-6769b-5p 1.06E−03− 369 hsa-miR-4689 1.17E−03 − 370 hsa-miR-6076 1.29E−03 − 371hsa-miR-92b-5p 1.68E−03 + 122 hsa-miR-550a-5p 1.80E−03 + 372hsa-miR-6774-5p 1.81E−03 + 373 hsa-miR-486-3p 2.00E−03 + 374hsa-miR-6806-5p 2.02E−03 + 64 hsa-miR-1228-3p 2.28E−03 + 375hsa-miR-6842-5p 2.35E−03 + 102 hsa-miR-4327 2.57E−03 − 376hsa-miR-6716-5p 2.70E−03 + 377 hsa-miR-557 2.87E−03 + 378 hsa-miR-46733.26E−03 + 379 hsa-miR-4674 3.91E−03 + 95 hsa-miR-4286 4.47E−03 − 86hsa-miR-4505 5.22E−03 − 380 hsa-miR-4442 5.97E−03 − 381 hsa-miR-1915-3p6.28E−03 + 382 hsa-miR-4687-3p 6.36E−03 − 383 hsa-miR-92b-3p 7.44E−03 +

Example 4

<Method for Evaluating Pancreatic Cancer-Specific DiscriminantPerformance by Combination of Plurality of Gene Markers Using Samples ofValidation Cohort>

In this Example, gene expression levels of miRNAs in sera were comparedbetween pancreatic cancer patients and a control group consisting ofhealthy subjects, colorectal cancer patients, stomach cancer patients,esophageal cancer patients, liver cancer patients, and benignpancreaticobiliary disease patients in the same way as the methoddescribed in Example 1 with respect to the training cohort as the samplegroup described in Reference Example 2 to select an additional genemarker for diagnosis. The additional gene marker for diagnosis (at leastone of SEQ ID NOs: 464 to 473 and 492 to 494) thus selected was combinedwith the gene markers selected in Example 1 to study a method forevaluating pancreatic cancer-specific discriminant performance.

Specifically, first, the miRNA expression levels of the training cohortand the validation cohort obtained in Reference Example 2 mentionedabove were combined and normalized by quantile normalization. Next,Fisher's discriminant analysis was conducted as to combinations of 1 to4 expression level measurement values comprising at least one or more ofthe expression level measurement values of the newly foundpolynucleotides consisting of the nucleotide sequences represented bySEQ ID NOs: 1 to 104, 349 to 383, 464 to 473, and 492 to 494 among thepolynucleotides consisting of the nucleotide sequences represented bySEQ ID NOs: 1 to 122, 349 to 383, 464 to 473, and 492 to 494, and thepolynucleotides consisting of the nucleotide sequences represented bySEQ ID NOs: 105 and 108, to construct a discriminant for determining thepresence or absence of pancreatic cancer. Next, accuracy, sensitivity,and specificity in the validation cohort were calculated using thediscriminant thus prepared, with the pancreatic cancer patient group asa positive sample group and the healthy subject group, the colorectalcancer patient group, the stomach cancer patient group, the esophagealcancer patient group, the liver cancer patient group, and the benignpancreaticobiliary disease patient group as negative sample groups. Thediscriminant performance of the selected polynucleotides was validatedusing independent samples.

Most of polynucleotides consisting of the nucleotide sequencesrepresented by these SEQ ID NOs (SEQ ID NOs: 1 to 122, 349 to 383, 464to 473, and 492 to 494 corresponding to the miRNA markers of Table 1) orcomplementary sequences thereof mentioned above were able to providerelatively high accuracy, sensitivity, and specificity in thedetermination of the presence or absence of pancreatic cancer, andfurthermore, were able to specifically discriminate pancreatic cancerfrom the other cancers. For example, among the combinations of multiplepolynucleotides selected from the group consisting of polynucleotidesconsisting of the nucleotide sequences represented by SEQ ID NOs: 2, 4,6, 7, 9, 10, 25, 28, 30, 31, 38, 48, 82, 103, 105, 108, and 464 orcomplementary sequences thereof (the cancer type-specific polynucleotidegroup 1) as polynucleotides capable of specifically binding to targetmarkers, combinations comprising at least one or more polynucleotidespreferably selected from the group consisting of polynucleotidesconsisting of the nucleotide sequences represented by SEQ ID NOs: 2, 4,7, 10, and 25 or complementary sequences thereof (the cancertype-specific polynucleotide group 2) included in the cancertype-specific polynucleotide group 1 were able to specificallydiscriminate pancreatic cancer from the other cancers with highaccuracy.

The number of the polynucleotides with cancer type specificity in thecombination mentioned above can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or morefor the combination. The combinations of 4 or more of thesepolynucleotides were able to exhibit discrimination accuracy of 80% orhigher.

The probes used in the measurement were the above-defined nucleic acidscapable of specifically binding to each polynucleotide as a targetmarker.

Specifically, the following results were obtained as the discriminationaccuracy of the measurement using the polynucleotide consisting of thenucleotide sequence represented by SEQ ID NO: 2 or a complementarysequence thereof as a target marker.

The measurement using one polynucleotide consisting of the nucleotidesequence represented by SEQ ID NO: 2 or a complementary sequence thereofexhibited accuracy of 91.1% in the training cohort and the highestaccuracy of 85.3% in the validation cohort (Table 8). Also, for example,the measurement using the combinations of two polynucleotides comprisingat least one polynucleotide consisting of the nucleotide sequencerepresented by SEQ ID NO: 2 or a complementary sequence thereofexhibited the highest accuracy of 93.0% in the training cohort and thehighest accuracy of 91.7% in the validation cohort (Table 9).Furthermore, for example, the measurement using the combinations ofthree polynucleotides comprising at least one polynucleotide consistingof the nucleotide sequence represented by SEQ ID NO: 2 or acomplementary sequence thereof exhibited the highest accuracy of 92.7%in the training cohort and the highest accuracy of 93.6% in thevalidation cohort (Table 10). Furthermore, for example, the measurementusing the combinations of four polynucleotides comprising at least onepolynucleotide consisting of the nucleotide sequence represented by SEQID NO: 2 or a complementary sequence thereof exhibited the highestaccuracy of 93.3% in the training cohort and the highest accuracy of96.2% in the validation cohort (Table 11).

Specifically, the following results were obtained as the discriminationaccuracy of the measurement using the polynucleotide consisting of thenucleotide sequence represented by SEQ ID NO: 4 or a complementarysequence thereof as a target marker.

The measurement using one polynucleotide consisting of the nucleotidesequence represented by SEQ ID NO: 4 or a complementary sequence thereofexhibited accuracy of 77.1% in the training cohort and the highestaccuracy of 78.8% in the validation cohort (Table 8). Also, for example,the measurement using the combinations of two polynucleotides comprisingat least one polynucleotide consisting of the nucleotide sequencerepresented by SEQ ID NO: 4 or a complementary sequence thereofexhibited the highest accuracy of 89.8% in the training cohort and thehighest accuracy of 88.5% in the validation cohort (Table 9).Furthermore, for example, the measurement using the combinations ofthree polynucleotides comprising at least one polynucleotide consistingof the nucleotide sequence represented by SEQ ID NO: 4 or acomplementary sequence thereof exhibited the highest accuracy of 92.7%in the training cohort and the highest accuracy of 91.7% in thevalidation cohort (Table 10). Furthermore, for example, the measurementusing the combinations of four polynucleotides comprising at least onepolynucleotide consisting of the nucleotide sequence represented by SEQID NO: 4 or a complementary sequence thereof exhibited the highestaccuracy of 92.7% in the training cohort and the highest accuracy of93.6% in the validation cohort (Table 11).

Specifically, the following results were obtained as the discriminationaccuracy of the measurement using the polynucleotide consisting of thenucleotide sequence represented by SEQ ID NO: 7 or a complementarysequence thereof as a target marker.

The measurement using one polynucleotide consisting of the nucleotidesequence represented by SEQ ID NO: 7 or a complementary sequence thereofexhibited accuracy of 86.7% in the training cohort and the highestaccuracy of 82.1% in the validation cohort (Table 8). Also, for example,the measurement using the combinations of two polynucleotides comprisingat least one polynucleotide consisting of the nucleotide sequencerepresented by SEQ ID NO: 7 or a complementary sequence thereofexhibited the highest accuracy of 90.2% in the training cohort and thehighest accuracy of 89.1% in the validation cohort (Table 9).Furthermore, for example, the measurement using the combinations ofthree polynucleotides comprising at least one polynucleotide consistingof the nucleotide sequence represented by SEQ ID NO: 7 or acomplementary sequence thereof exhibited the highest accuracy of 92.7%in the training cohort and the highest accuracy of 93.6% in thevalidation cohort (Table 10). Furthermore, for example, the measurementusing the combinations of four polynucleotides comprising at least onepolynucleotide consisting of the nucleotide sequence represented by SEQID NO: 7 or a complementary sequence thereof exhibited the highestaccuracy of 93.3% in the training cohort and the highest accuracy of96.2% in the validation cohort (Table 11).

Specifically, the following results were obtained as the discriminationaccuracy of the measurement using the polynucleotide consisting of thenucleotide sequence represented by SEQ ID NO: 10 or a complementarysequence thereof as a target marker.

The measurement using one polynucleotide consisting of the nucleotidesequence represented by SEQ ID NO: 10 or a complementary sequencethereof exhibited accuracy of 77.1% in the training cohort and thehighest accuracy of 68.6% in the validation cohort (Table 8). Also, forexample, the measurement using the combinations of two polynucleotidescomprising at least one polynucleotide consisting of the nucleotidesequence represented by SEQ ID NO: 10 or a complementary sequencethereof exhibited the highest accuracy of 90.8% in the training cohortand the highest accuracy of 89.7% in the validation cohort (Table 9).Furthermore, for example, the measurement using the combinations ofthree polynucleotides comprising at least one polynucleotide consistingof the nucleotide sequence represented by SEQ ID NO: 10 or acomplementary sequence thereof exhibited the highest accuracy of 93.0%in the training cohort and the highest accuracy of 91.7% in thevalidation cohort (Table 10). Furthermore, for example, the measurementusing the combinations of four polynucleotides comprising at least onepolynucleotide consisting of the nucleotide sequence represented by SEQID NO: 10 or a complementary sequence thereof exhibited the highestaccuracy of 93.7% in the training cohort and the highest accuracy of93.6% in the validation cohort (Table 11).

Specifically, the following results were obtained as the discriminationaccuracy of the measurement using the polynucleotide consisting of thenucleotide sequence represented by SEQ ID NO: 25 or a complementarysequence thereof as a target marker.

The measurement using one polynucleotide consisting of the nucleotidesequence represented by SEQ ID NO: 25 or a complementary sequencethereof exhibited accuracy of 82.2% in the training cohort and thehighest accuracy of 75.6% in the validation cohort (Table 8). Also, forexample, the measurement using the combinations of two polynucleotidescomprising at least one polynucleotide consisting of the nucleotidesequence represented by SEQ ID NO: 25 or a complementary sequencethereof exhibited the highest accuracy of 90.8% in the training cohortand the highest accuracy of 87.8% in the validation cohort (Table 9).Furthermore, for example, the measurement using the combinations ofthree polynucleotides comprising at least one polynucleotide consistingof the nucleotide sequence represented by SEQ ID NO: 25 or acomplementary sequence thereof exhibited the highest accuracy of 91.1%in the training cohort and the highest accuracy of 91.0% in thevalidation cohort (Table 10). Furthermore, for example, the measurementusing the combinations of four polynucleotides comprising at least onepolynucleotide consisting of the nucleotide sequence represented by SEQID NO: 25 or a complementary sequence thereof exhibited the highestaccuracy of 92.7% in the training cohort and the highest accuracy of93.6% in the validation cohort (Table 11).

The expression level measurement values of the nucleotide sequencesrepresented by SEQ ID NOs: 2, 7, 9, and 105 were compared among 67pancreatic cancer patients, 93 healthy subjects, 35 colorectal cancerpatients, 37 stomach cancer patients, 32 esophageal cancer patients, 38liver cancer patients, and 13 benign pancreaticobiliary disease patientsin the training cohort. As a result, a scatter diagram thatsignificantly separated the discriminant score of the pancreatic cancerpatient group from the other discriminant scores was obtained in thetraining cohort (see the upper diagram of FIG. 4). These results werealso reproducible in the validation cohort (see the lower diagram ofFIG. 4).

Tables 8, 9, 10, and 11 mentioned above are as follows.

TABLE 8 Training cohort Validation cohort Accuracy SensitivitySpecificity Accuracy Sensitivity Specificity SEQ ID NO: (%) (%) (%) (%)(%) (%) 2 91.1 83.6 93.1 85.3 69.7 89.4 4 77.1 77.6 77 78.8 81.8 78 6 8176.1 82.3 75 60.6 78.9 7 86.7 89.6 85.9 82.1 87.9 80.5 9 78.4 85.1 76.675 90.9 70.7 10 77.1 82.1 75.8 68.6 75.8 66.7 25 82.2 86.6 81 75.6 72.776.4 28 68.9 74.6 67.3 67.9 69.7 67.5 30 70.2 70.1 70.2 76.3 72.7 77.231 75.6 68.7 77.4 74.4 69.7 75.6 38 77.1 67.2 79.8 73.7 63.6 76.4 48 7477.6 73 74.4 66.7 76.4 82 57.5 59.7 56.9 62.2 63.6 61.8 103 58.1 49.360.5 52.6 48.5 53.7 108 74.6 70.1 75.8 71.2 69.7 71.5 464 68.3 53.7 72.267.3 57.6 69.9

TABLE 9 Training cohort Validation cohort Accuracy SensitivitySpecificity Accuracy Sensitivity Specificity SEQ ID NO: (%) (%) (%) (%)(%) (%) 2_48 93 83.6 95.6 91.7 81.8 94.3 2_10 90.8 86.6 91.9 89.7 87.990.2 2_465 89.5 83.6 91.1 89.7 87.9 90.2 2_9 90.5 85.1 91.9 89.7 84.891.1 2_30 91.7 85.1 93.5 89.7 81.8 91.9 2_61 89.8 79.1 92.7 89.7 81.891.9 2_101 90.5 82.1 92.7 89.7 78.8 92.7 2_7 90.2 80.6 92.7 89.1 84.890.2 2_28 90.5 83.6 92.3 89.1 84.8 90.2 2_4 89.8 83.6 91.5 88.5 81.890.2 2_68 90.8 85.1 92.3 88.5 81.8 90.2 2_25 90.8 86.6 91.9 87.8 81.889.4

TABLE 10 Training cohort Validation cohort Accuracy SensitivitySpecificity Accuracy Sensitivity Specificity SEQ ID NO: (%) (%) (%) (%)(%) (%) 2_7_101 92.7 86.6 94.4 93.6 93.9 93.5 2_48_68 93.7 83.6 96.493.6 78.8 97.6 2_7_82 92.7 82.1 95.6 92.9 87.9 94.3 2_6_48 93.7 85.1 9692.9 87.9 94.3 2_48_17 92.7 83.6 95.2 92.9 84.8 95.1 2_48_101 93.3 85.195.6 92.9 84.8 95.1 2_465_467 90.8 82.1 93.1 92.3 93.9 91.9 2_7_48 92.483.6 94.8 92.3 84.8 94.3 2_48_38 92.7 82.1 95.6 92.3 84.8 94.3 2_48_2292.7 85.1 94.8 92.3 84.8 94.3 2_48_30 94.3 88.1 96 92.3 84.8 94.32_48_53 93.3 83.6 96 92.3 84.8 94.3 2_48_47 93 85.1 95.2 92.3 84.8 94.32_48_365 93 85.1 95.2 92.3 84.8 94.3 2_38_101 91.4 85.1 93.1 92.3 84.894.3 2_31_101 91.7 82.1 94.4 92.3 81.8 95.1 2_48_82 93 83.6 95.6 92.381.8 95.1 2_9_103 91.4 83.6 93.5 91.7 93.9 91.1 2_9_469 90.2 85.1 91.591.7 93.9 91.1 2_38_465 91.7 85.1 93.5 91.7 87.9 92.7 2_465_373 89.883.6 91.5 91.7 87.9 92.7 2_61_365 88.9 79.1 91.5 91.7 87.9 92.7 2_31_4893.7 86.6 95.6 91.7 84.8 93.5 2_6_101 91.7 85.1 93.5 91.7 84.8 93.52_48_103 93.3 85.1 95.6 91.7 84.8 93.5 2_68_101 91.7 85.1 93.5 91.7 84.893.5 2_465_101 90.8 82.1 93.1 91.7 84.8 93.5 2_61_101 90.5 80.6 93.191.7 84.8 93.5 2_4_48 92.7 82.1 95.6 91.7 81.8 94.3 2_10_48 93 85.1 95.291.7 81.8 94.3 2_9_48 93.3 85.1 95.6 91.7 81.8 94.3 2_48_51 93 83.6 95.691.7 81.8 94.3 2_48_465 93 83.6 95.6 91.7 81.8 94.3 2_48_108 93 82.1 9691.7 81.8 94.3 2_48_28 93 83.6 95.6 91.7 81.8 94.3 2_48_373 93 80.6 96.491.7 81.8 94.3 2_48_466 92.7 82.1 95.6 91.7 81.8 94.3 2_48_61 93 83.695.6 91.7 81.8 94.3 2_48_467 93.3 82.1 96.4 91.7 81.8 94.3 2_48_464 9383.6 95.6 91.7 81.8 94.3 2_48_382 92.7 83.3 95.2 91.7 81.8 94.3 2_48_37093 82.1 96 91.7 81.8 94.3 2_101_365 90.5 79.1 93.5 91.7 81.8 94.32_10_365 89.5 83.6 91.1 91 93.9 90.2 2_7_465 91.1 82.1 93.5 91 90.9 91.12_7_61 90.2 82.1 92.3 91 90.9 91.1 2_9_467 90.5 85.1 91.9 91 90.9 91.12_465_469 89.2 83.6 90.7 91 90.9 91.1 2_25_30 91.1 86.6 92.3 91 87.991.9 2_7_466 90.2 80.6 92.7 91 87.9 91.9 2_7_47 89.8 82.1 91.9 91 87.991.9 2_10_82 90.8 88.1 91.5 91 87.9 91.9 2_9_47 90.8 85.1 92.3 91 87.991.9 2_7_68 92.4 85.1 94.4 91 84.8 92.7 2_7_22 91.7 83.6 94 91 84.8 92.72_7_100 90.2 80.6 92.7 91 84.8 92.7 2_10_101 92.7 86.6 94.4 91 84.8 92.72_9_101 92.4 85.1 94.4 91 84.8 92.7 2_48_359 93 82.1 96 91 84.8 92.72_38_103 91.4 85.1 93.1 91 84.8 92.7 2_465_82 90.5 85.1 91.9 91 84.892.7 2_28_382 91.1 83.3 93.1 91 84.8 92.7 2_28_82 91.7 85.1 93.5 91 84.892.7 2_30_101 92.1 83.6 94.4 91 84.8 92.7 2_25_48 93 85.1 95.2 91 81.893.5 2_48_90 94 88.1 95.6 91 81.8 93.5 2_48_468 93 83.6 95.6 91 81.893.5 2_48_118 92.4 85.1 94.4 91 81.8 93.5 2_51_101 90.8 83.6 92.7 9181.8 93.5 2_38_30 90.8 82.1 93.1 91 81.8 93.5 2_61_469 90.5 80.6 93.1 9181.8 93.5 2_53_101 91.1 83.6 93.1 91 81.8 93.5 2_101_464 90.2 80.6 92.791 81.8 93.5 2_101_118 90.2 82.1 92.3 91 81.8 93.5 2_101_469 90.5 82.192.7 91 81.8 93.5 2_101_47 91.4 83.6 93.5 91 78.8 94.3 2_101_100 90.582.1 92.7 91 78.8 94.3 2_465_365 88.9 82.1 90.7 90.4 93.9 89.4 2_7_991.4 83.6 93.5 90.4 90.9 90.2 2_7_28 91.1 82.1 93.5 90.4 90.9 90.22_7_53 91.1 83.6 93.1 90.4 90.9 90.2 2_7_365 89.8 80.6 92.3 90.4 90.990.2 2_10_9 91.1 86.6 92.3 90.4 90.9 90.2 2_9_365 89.5 83.6 91.1 90.490.9 90.2 2_9_82 92.1 86.6 93.5 90.4 90.9 90.2 2_465_47 89.8 83.6 91.590.4 90.9 90.2 2_25_61 91.1 85.1 92.7 90.4 87.9 91.1 2_7_17 90.5 80.693.1 90.4 87.9 91.1 2_7_464 89.2 79.1 91.9 90.4 87.9 91.1 2_7_103 92.485.1 94.4 90.4 87.9 91.1 2_7_469 90.2 80.6 92.7 90.4 87.9 91.1 2_10_3091.7 88.1 92.7 90.4 87.9 91.1 2_10_61 90.5 85.1 91.9 90.4 87.9 91.12_9_31 90.2 85.1 91.5 90.4 87.9 91.1 2_9_28 91.1 83.6 93.1 90.4 87.991.1 2_9_468 90.2 85.1 91.5 90.4 87.9 91.1 2_9_370 90.8 85.1 92.3 90.487.9 91.1 2_9_100 89.8 85.1 91.1 90.4 87.9 91.1 2_38_61 90.8 83.6 92.790.4 87.9 91.1 2_7_382 92 81.8 94.8 90.4 84.8 91.9 2_9_61 90.5 83.6 92.390.4 84.8 91.9 2_48_100 93.7 85.1 96 90.4 84.8 91.9 2_48_469 93 82.1 9690.4 84.8 91.9 2_51_30 91.7 86.6 93.1 90.4 84.8 91.9 2_68_28 92.1 83.694.4 90.4 84.8 91.9 2_465_30 91.1 85.1 92.7 90.4 84.8 91.9 2_465_61 90.885.1 92.3 90.4 84.8 91.9 2_28_30 92.4 85.1 94.4 90.4 84.8 91.9 2_28_4790.2 83.6 91.9 90.4 84.8 91.9 2_28_370 91.1 83.6 93.1 90.4 84.8 91.92_22_61 90.5 80.6 93.1 90.4 84.8 91.9 2_30_365 90.5 82.1 92.7 90.4 84.891.9 2_30_100 91.4 85.1 93.1 90.4 84.8 91.9 2_61_467 89.5 80.6 91.9 90.484.8 91.9 2_61_464 89.5 77.6 92.7 90.4 84.8 91.9 2_25_101 91.1 85.1 92.790.4 81.8 92.7 2_4_101 90.5 80.6 93.1 90.4 81.8 92.7 2_28_101 91.7 83.694 90.4 81.8 92.7 2_22_101 90.2 80.6 92.7 90.4 81.8 92.7 2_30_53 90.882.1 93.1 90.4 81.8 92.7 2_61_47 88.9 80.6 91.1 90.4 81.8 92.7 2_108_10191.1 82.1 93.5 90.4 78.8 93.5 2_28_17 92.1 85.1 94 90.4 78.8 93.52_373_101 90.5 82.1 92.7 90.4 78.8 93.5 2_466_101 90.8 82.1 93.1 90.478.8 93.5 2_101_468 90.5 82.1 92.7 90.4 78.8 93.5 2_101_370 89.8 79.192.7 90.4 78.8 93.5 2_101_82 91.1 82.1 93.5 90.4 78.8 93.5 2_7_10 91.785.1 93.5 89.7 90.9 89.4 2_9_38 91.7 86.6 93.1 89.7 90.9 89.4 2_25_46589.2 85.1 90.3 89.7 87.9 90.2 2_25_28 90.8 85.1 92.3 89.7 87.9 90.22_7_38 92.4 82.1 95.2 89.7 87.9 90.2 2_7_108 90.2 80.6 92.7 89.7 87.990.2 2_7_118 89.5 83.6 91.1 89.7 87.9 90.2 2_4_465 89.5 83.6 91.1 89.787.9 90.2 2_10_465 91.7 86.6 93.1 89.7 87.9 90.2 2_10_28 91.1 86.6 92.389.7 87.9 90.2 2_10_466 90.8 86.6 91.9 89.7 87.9 90.2 2_10_370 91.1 86.692.3 89.7 87.9 90.2 2_10_359 90.8 86.6 91.9 89.7 87.9 90.2 2_10_469 91.786.6 93.1 89.7 87.9 90.2 2_9_6 89.8 86.6 90.7 89.7 87.9 90.2 2_9_46590.5 83.6 92.3 89.7 87.9 90.2 2_9_382 90.8 84.8 92.3 89.7 87.9 90.22_6_365 89.5 83.6 91.1 89.7 87.9 90.2 2_51_465 89.5 83.6 91.1 89.7 87.990.2 2_465_108 89.8 83.6 91.5 89.7 87.9 90.2 2_465_28 90.8 85.1 92.389.7 87.9 90.2 2_465_22 89.2 83.6 90.7 89.7 87.9 90.2 2_465_17 89.5 83.691.1 89.7 87.9 90.2 2_465_466 89.8 83.6 91.5 89.7 87.9 90.2 2_465_46489.8 85.1 91.1 89.7 87.9 90.2 2_465_368 89.5 83.6 91.1 89.7 87.9 90.22_465_359 89.5 83.6 91.1 89.7 87.9 90.2 2_465_100 89.8 85.1 91.1 89.787.9 90.2 2_25_47 89.8 85.1 91.1 89.7 84.8 91.1 2_7_4 90.2 80.6 92.789.7 84.8 91.1 2_7_31 90.2 80.6 92.7 89.7 84.8 91.1 2_7_373 89.8 79.192.7 89.7 84.8 91.1 2_7_370 90.5 80.6 93.1 89.7 84.8 91.1 2_4_61 89.880.6 92.3 89.7 84.8 91.1 2_10_108 90.8 86.6 91.9 89.7 84.8 91.1 2_10_11890.5 86.6 91.5 89.7 84.8 91.1 2_9_108 90.5 85.1 91.9 89.7 84.8 91.12_9_22 90.5 85.1 91.9 89.7 84.8 91.1 2_9_30 91.7 85.1 93.5 89.7 84.891.1 2_9_466 90.5 85.1 91.9 89.7 84.8 91.1 2_9_368 90.5 85.1 91.9 89.784.8 91.1 2_51_61 90.8 83.6 92.7 89.7 84.8 91.1 2_38_382 91.1 84.8 92.789.7 84.8 91.1 2_465_53 90.5 85.1 91.9 89.7 84.8 91.1 2_108_61 89.8 82.191.9 89.7 84.8 91.1 2_28_467 91.4 85.1 93.1 89.7 84.8 91.1 2_28_468 91.485.1 93.1 89.7 84.8 91.1 2_28_469 91.1 83.6 93.1 89.7 84.8 91.1 2_22_10389.8 83.6 91.5 89.7 84.8 91.1 2_466_61 90.5 82.1 92.7 89.7 84.8 91.12_7_30 92.1 88.1 93.1 89.7 81.8 91.9 2_4_30 91.1 82.1 93.5 89.7 81.891.9 2_9_373 90.2 85.1 91.5 89.7 81.8 91.9 2_9_464 90.5 85.1 91.9 89.781.8 91.9 2_31_465 89.8 83.6 91.5 89.7 81.8 91.9 2_31_61 89.8 79.1 92.789.7 81.8 91.9 2_68_38 92.1 85.1 94 89.7 81.8 91.9 2_465_103 91.1 83.693.1 89.7 81.8 91.9 2_28_373 91.7 85.1 93.5 89.7 81.8 91.9 2_28_61 90.885.1 92.3 89.7 81.8 91.9 2_28_368 91.4 85.1 93.1 89.7 81.8 91.9 2_28_11890.2 85.1 91.5 89.7 81.8 91.9 2_373_61 90.2 80.6 92.7 89.7 81.8 91.92_22_30 91.4 85.1 93.1 89.7 81.8 91.9 2_30_17 91.7 85.1 93.5 89.7 81.891.9 2_30_61 91.7 85.1 93.5 89.7 81.8 91.9 2_30_368 91.4 83.6 93.5 89.781.8 91.9 2_30_118 92.1 85.1 94 89.7 81.8 91.9 2_30_359 91.7 85.1 93.589.7 81.8 91.9 2_30_103 92.4 83.6 94.8 89.7 81.8 91.9 2_17_61 89.8 79.192.7 89.7 81.8 91.9 2_61_370 89.8 79.1 92.7 89.7 81.8 91.9 2_61_368 89.877.6 93.1 89.7 81.8 91.9 2_61_118 90.2 80.6 92.7 89.7 81.8 91.9 2_61_8289.8 76.1 93.5 89.7 81.8 91.9 2_17_101 90.5 82.1 92.7 89.7 78.8 92.72_467_101 90.5 82.1 92.7 89.7 78.8 92.7 2_101_382 91.1 81.8 93.5 89.778.8 92.7 2_101_368 90.5 82.1 92.7 89.7 78.8 92.7 2_101_359 90.5 82.192.7 89.7 78.8 92.7 2_101_103 90.5 82.1 92.7 89.7 78.8 92.7 2_90_10190.8 82.1 93.1 89.7 75.8 93.5 2_25_9 90.2 85.1 91.5 89.1 87.9 89.42_25_53 89.8 85.1 91.1 89.1 87.9 89.4 2_7_6 90.8 85.1 92.3 89.1 87.989.4 2_10_22 90.8 86.6 91.9 89.1 87.9 89.4 2_10_53 90.8 86.6 91.9 89.187.9 89.4 2_10_47 89.8 86.6 90.7 89.1 87.9 89.4 2_9_51 90.5 85.1 91.989.1 87.9 89.4 2_25_7 91.4 83.6 93.5 89.1 84.8 90.2 2_25_68 91.4 86.692.7 89.1 84.8 90.2 2_25_17 90.5 86.6 91.5 89.1 84.8 90.2 2_25_365 89.583.6 91.1 89.1 84.8 90.2 2_7_467 90.8 80.6 93.5 89.1 84.8 90.2 2_7_46890.5 80.6 93.1 89.1 84.8 90.2 2_7_368 90.2 80.6 92.7 89.1 84.8 90.22_7_359 90.8 83.6 92.7 89.1 84.8 90.2 2_4_10 90.8 86.6 91.9 89.1 84.890.2 2_4_9 90.5 85.1 91.9 89.1 84.8 90.2 2_4_28 90.5 83.6 92.3 89.1 84.890.2 2_4_90 90.5 82.1 92.7 89.1 84.8 90.2 2_10_31 91.1 86.6 92.3 89.184.8 90.2 2_10_51 90.8 86.6 91.9 89.1 84.8 90.2 2_10_382 90.4 86.4 91.589.1 84.8 90.2 2_9_53 91.1 85.1 92.7 89.1 84.8 90.2 2_9_359 90.5 85.191.9 89.1 84.8 90.2 2_51_28 90.8 83.6 92.7 89.1 84.8 90.2 2_51_90 90.880.6 93.5 89.1 84.8 90.2 2_68_61 91.4 82.1 94 89.1 84.8 90.2 2_38_2890.8 85.1 92.3 89.1 84.8 90.2 2_108_30 91.7 88.1 92.7 89.1 84.8 90.22_28_466 90.5 83.6 92.3 89.1 84.8 90.2 2_28_359 90.8 83.6 92.7 89.1 84.890.2 2_28_100 90.8 85.1 92.3 89.1 84.8 90.2 2_30_464 91.4 82.1 94 89.184.8 90.2 2_468_365 88.9 80.6 91.1 89.1 84.8 90.2 2_25_82 90.8 86.6 91.989.1 81.8 91.1 2_7_51 89.2 77.6 92.3 89.1 81.8 91.1 2_4_103 91.1 82.193.5 89.1 81.8 91.1 2_31_68 90.2 83.6 91.9 89.1 81.8 91.1 2_31_30 91.182.1 93.5 89.1 81.8 91.1 2_6_30 91.7 88.1 92.7 89.1 81.8 91.1 2_48_36893 85.1 95.2 89.1 81.8 91.1 2_51_373 89.8 83.6 91.5 89.1 81.8 91.12_68_47 90.5 85.1 91.9 89.1 81.8 91.1 2_68_368 91.4 85.1 93.1 89.1 81.891.1 2_68_100 91.1 85.1 92.7 89.1 81.8 91.1 2_68_103 90.8 85.1 92.3 89.181.8 91.1 2_38_82 90.5 85.1 91.9 89.1 81.8 91.1 2_108_28 91.1 83.6 93.189.1 81.8 91.1 2_108_17 91.4 83.6 93.5 89.1 81.8 91.1 2_373_30 92.4 86.694 89.1 81.8 91.1 2_30_466 90.8 85.1 92.3 89.1 81.8 91.1 2_30_370 91.785.1 93.5 89.1 81.8 91.1 2_30_82 91.4 85.1 93.1 89.1 81.8 91.1 2_466_10391.4 85.1 93.1 89.1 81.8 91.1 2_61_53 91.1 82.1 93.5 89.1 81.8 91.12_61_468 89.8 79.1 92.7 89.1 81.8 91.1 2_61_359 89.8 79.1 92.7 89.1 81.891.1 2_9_17 90.5 85.1 91.9 89.1 78.8 91.9 2_28_103 91.4 83.6 93.5 89.178.8 91.9 2_90_100 90.5 80.6 93.1 89.1 78.8 91.9 2_61_382 90.1 80.3 92.789.1 78.8 91.9 2_100_103 90.8 83.6 92.7 89.1 75.8 92.7 2_25_10 90.2 88.190.7 88.5 84.8 89.4 2_25_464 90.5 86.6 91.5 88.5 84.8 89.4 2_4_82 90.585.1 91.9 88.5 84.8 89.4 2_10_467 90.8 86.6 91.9 88.5 84.8 89.4 2_10_46491.1 86.6 92.3 88.5 84.8 89.4 2_10_368 90.8 86.6 91.9 88.5 84.8 89.42_9_68 92.1 86.6 93.5 88.5 84.8 89.4 2_6_51 89.8 85.1 91.1 88.5 84.889.4 2_6_61 88.9 83.6 90.3 88.5 84.8 89.4 2_6_464 89.5 85.1 90.7 88.584.8 89.4 2_6_100 90.2 85.1 91.5 88.5 84.8 89.4 2_51_365 89.5 83.6 91.188.5 84.8 89.4 2_38_90 90.8 80.6 93.5 88.5 84.8 89.4 2_38_365 88.6 82.190.3 88.5 84.8 89.4 2_108_365 89.2 83.6 90.7 88.5 84.8 89.4 2_108_8291.1 85.1 92.7 88.5 84.8 89.4 2_28_365 89.2 83.6 90.7 88.5 84.8 89.42_22_467 89.8 85.1 91.1 88.5 84.8 89.4 2_22_382 89.8 83.3 91.5 88.5 84.889.4 2_22_82 90.5 85.1 91.9 88.5 84.8 89.4 2_466_365 89.2 83.6 90.7 88.584.8 89.4 2_25_38 91.4 86.6 92.7 88.5 81.8 90.2 2_25_373 90.5 86.6 91.588.5 81.8 90.2 2_25_468 90.8 85.1 92.3 88.5 81.8 90.2 2_4_464 90.2 83.691.9 88.5 81.8 90.2 2_4_468 89.8 83.6 91.5 88.5 81.8 90.2 2_4_47 90.283.6 91.9 88.5 81.8 90.2 2_10_373 90.2 86.6 91.1 88.5 81.8 90.2 2_10_46890.8 86.6 91.9 88.5 81.8 90.2 2_9_90 90.5 82.1 92.7 88.5 81.8 90.22_9_118 90.5 85.1 91.9 88.5 81.8 90.2 2_31_38 90.2 85.1 91.5 88.5 81.890.2 2_6_68 91.7 85.1 93.5 88.5 81.8 90.2 2_51_82 90.2 83.6 91.9 88.581.8 90.2 2_68_373 90.8 85.1 92.3 88.5 81.8 90.2 2_68_464 89.8 83.6 91.588.5 81.8 90.2 2_38_464 90.2 85.1 91.5 88.5 81.8 90.2 2_38_359 91.4 85.193.1 88.5 81.8 90.2 2_465_90 90.2 80.6 92.7 88.5 81.8 90.2 2_465_46890.2 83.6 91.9 88.5 81.8 90.2 2_465_370 89.8 82.1 91.9 88.5 81.8 90.22_465_118 90.8 86.6 91.9 88.5 81.8 90.2 2_28_464 91.1 85.1 92.7 88.581.8 90.2 2_22_90 90.2 80.6 92.7 88.5 81.8 90.2 2_22_118 90.8 83.6 92.788.5 81.8 90.2 2_30_467 91.7 85.1 93.5 88.5 81.8 90.2 2_30_468 92.1 85.194 88.5 81.8 90.2 2_30_47 92.1 86.6 93.5 88.5 81.8 90.2 2_61_103 90.277.6 93.5 88.5 81.8 90.2 2_467_365 87.9 80.6 89.9 88.5 81.8 90.22_53_365 88.9 80.6 91.1 88.5 81.8 90.2 2_53_103 91.1 82.1 93.5 88.5 81.890.2 2_31_382 89.5 80.3 91.9 88.5 78.8 91.1 2_31_103 89.5 79.1 92.3 88.578.8 91.1 2_68_30 92.4 85.1 94.4 88.5 78.8 91.1 2_68_370 90.2 83.6 91.988.5 78.8 91.1 2_68_82 91.4 85.1 93.1 88.5 78.8 91.1 2_38_17 90.5 85.191.9 88.5 78.8 91.1 2_38_100 90.2 85.1 91.5 88.5 78.8 91.1 2_90_61 90.579.1 93.5 88.5 78.8 91.1 2_90_464 90.5 80.6 93.1 88.5 78.8 91.1 2_90_37090.8 80.6 93.5 88.5 78.8 91.1 2_30_382 91.1 81.8 93.5 88.5 78.8 91.12_30_469 91.1 83.6 93.1 88.5 78.8 91.1 2_61_100 89.8 80.6 92.3 88.5 78.891.1 2_368_82 90.8 83.6 92.7 88.5 78.8 91.1 2_100_82 90.2 83.6 91.9 88.578.8 91.1 2_90_368 90.8 80.6 93.5 88.5 75.8 91.9 2_90_118 90.2 80.6 92.788.5 75.8 91.9 7_4_82 90.2 85.1 91.5 90.4 90.9 90.2 7_68_61 89.8 88.190.3 89.7 87.9 90.2 7_38_101 90.2 86.6 91.1 89.7 87.9 90.2 7_30_101 87.689.6 87.1 89.1 90.9 88.6 7_30_82 87.9 89.6 87.5 89.1 87.9 89.4 2_25_791.4 83.6 93.5 89.1 84.8 90.2 7_68_28 89.2 85.1 90.3 89.1 84.8 90.27_4_103 88.9 88.1 89.1 88.5 87.9 88.6 7_10_31 86.3 79.1 88.3 88.5 87.988.6 7_68_38 90.5 86.6 91.5 88.5 84.8 89.4 7_68_47 88.6 85.1 89.5 88.584.8 89.4 7_30_103 87.9 89.6 87.5 88.5 81.8 90.2 25_7_47 87.9 86.6 88.390.4 87.9 91.1 25_7_373 89.2 91 88.7 89.1 93.9 87.8 25_7_61 87.6 89.687.1 89.1 93.9 87.8 25_7_48 89.2 88.1 89.5 89.1 87.9 89.4 25_7_467 89.289.6 89.1 88.5 90.9 87.8 25_7_464 87.9 91 87.1 88.5 90.9 87.8 25_7_11888.9 91 88.3 88.5 90.9 87.8

TABLE 11 Training cohort Validation cohort Accuracy SensitivitySpecificity Accuracy Sensitivity Specificity SEQ ID NO: (%) (%) (%) (%)(%) (%) 2_7_61_82 93.3 85.1 95.6 96.2 97 95.9 2_7_82_103 93 83.6 95.695.5 87.9 97.6 2_7_47_82 92.4 83.6 94.8 94.9 93.9 95.1 2_7_82_101 94.688.1 96.4 94.9 87.9 96.7 2_7_9_101 92.7 86.6 94.4 94.2 93.9 94.32_7_31_101 93 86.6 94.8 94.2 93.9 94.3 2_7_51_101 92.4 83.6 94.8 94.293.9 94.3 2_38_53_465 92.1 85.1 94 94.2 93.9 94.3 2_7_9_82 93 85.1 95.294.2 90.9 95.1 2_7_48_103 93.7 85.1 96 94.2 90.9 95.1 2_7_101_466 92.182.1 94.8 94.2 90.9 95.1 2_7_47_101 92.4 85.1 94.4 94.2 90.9 95.12_7_48_51 93 86.6 94.8 94.2 87.9 95.9 2_7_48_469 92.7 83.6 95.2 94.287.9 95.9 2_38_82_101 91.4 83.6 93.5 94.2 87.9 95.9 2_7_48_82 94 83.696.8 94.2 84.8 96.7 2_48_68_467 94 85.1 96.4 94.2 81.8 97.6 2_48_68_37093.3 83.6 96 94.2 81.8 97.6 2_7_25_101 92.7 86.6 94.4 93.6 93.9 93.52_7_101_465 92.7 86.6 94.4 93.6 93.9 93.5 2_7_61_101 92.7 86.6 94.4 93.693.9 93.5 2_7_61_103 92.7 83.6 95.2 93.6 93.9 93.5 2_7_101_368 92.4 85.194.4 93.6 93.9 93.5 2_7_101_365 92.7 85.1 94.8 93.6 93.9 93.52_38_51_465 91.1 85.1 92.7 93.6 93.9 93.5 2_28_465_467 92.7 86.6 94.493.6 93.9 93.5 2_365_373_465 90.2 83.6 91.9 93.6 93.9 93.5 2_100_465_46791.4 85.1 93.1 93.6 93.9 93.5 2_7_10_82 93.7 83.6 96.4 93.6 90.9 94.32_7_38_48 93.3 83.6 96 93.6 90.9 94.3 2_7_48_359 93.3 83.6 96 93.6 90.994.3 2_7_101_373 92.7 85.1 94.8 93.6 90.9 94.3 2_7_82_118 92.4 83.6 94.893.6 90.9 94.3 2_7_82_365 92.1 80.6 95.2 93.6 90.9 94.3 2_6_48_359 93.783.6 96.4 93.6 90.9 94.3 2_38_82_465 92.1 85.1 94 93.6 90.9 94.32_38_101_365 92.1 83.6 94.4 93.6 90.9 94.3 2_7_25_82 93.7 85.1 96 93.687.9 95.1 2_7_48_466 92.4 85.1 94.4 93.6 87.9 95.1 2_7_48_467 93 83.695.6 93.6 87.9 95.1 2_7_82_465 92.7 82.1 95.6 93.6 87.9 95.1 2_7_30_8293 85.1 95.2 93.6 87.9 95.1 2_7_101_382 93.3 84.8 95.6 93.6 87.9 95.12_30_31_48 94.6 89.6 96 93.6 87.9 95.1 2_31_48_53 93.7 86.6 95.6 93.687.9 95.1 2_31_48_82 93.3 86.6 95.2 93.6 87.9 95.1 2_31_53_101 91.4 80.694.4 93.6 87.9 95.1 2_38_48_101 92.7 83.6 95.2 93.6 87.9 95.12_48_465_467 93.3 83.6 96 93.6 87.9 95.1 2_17_48_365 92.7 83.6 95.2 93.687.9 95.1 2_28_68_101 93.3 86.6 95.2 93.6 87.9 95.1 2_30_38_101 93 86.694.8 93.6 87.9 95.1 2_17_25_48 92.7 83.6 95.2 93.6 84.8 95.9 2_7_47_6891.7 83.6 94 93.6 84.8 95.9 2_7_28_82 93.7 85.1 96 93.6 84.8 95.92_7_382_82 92.7 81.8 95.6 93.6 84.8 95.9 2_4_38_48 92.7 82.1 95.6 93.684.8 95.9 2_48_465_466 93 83.6 95.6 93.6 84.8 95.9 2_48_101_108 93 83.695.6 93.6 84.8 95.9 2_22_48_82 92.4 85.1 94.4 93.6 84.8 95.9 2_30_48_46793.3 82.1 96.4 93.6 84.8 95.9 2_30_48_82 94.6 89.6 96 93.6 84.8 95.92_17_48_101 92.7 83.6 95.2 93.6 84.8 95.9 2_48_82_101 93.3 85.1 95.693.6 84.8 95.9 2_38_101_359 91.7 85.1 93.5 93.6 84.8 95.9 2_82_101_10891.4 82.1 94 93.6 84.8 95.9 2_31_48_68 94 86.6 96 93.6 81.8 96.72_6_48_68 94.3 85.1 96.8 93.6 81.8 96.7 2_38_48_68 93.3 83.6 96 93.681.8 96.7 2_48_68_90 94 86.6 96 93.6 81.8 96.7 2_25_48_68 93.7 83.6 96.493.6 78.8 97.6 2_4_48_68 93.7 83.6 96.4 93.6 78.8 97.6 2_48_51_68 93.783.6 96.4 93.6 78.8 97.6 2_48_68_465 93.7 83.6 96.4 93.6 78.8 97.62_48_68_108 93.7 83.6 96.4 93.6 78.8 97.6 2_48_68_373 94 83.6 96.8 93.678.8 97.6 2_48_68_466 93.7 83.6 96.4 93.6 78.8 97.6 2_48_68_101 94 85.196.4 93.6 78.8 97.6 2_48_68_103 93.7 83.6 96.4 93.6 78.8 97.6 2_7_61_36589.8 79.1 92.7 92.9 97 91.9 2_10_82_365 91.1 85.1 92.7 92.9 97 91.92_9_82_467 92.7 88.1 94 92.9 97 91.9 2_7_10_101 93.3 86.6 95.2 92.9 93.992.7 2_7_38_101 93.3 86.6 95.2 92.9 93.9 92.7 2_7_61_466 90.5 80.6 93.192.9 93.9 92.7 2_51_465_467 90.8 82.1 93.1 92.9 93.9 92.7 2_38_465_46691.4 83.6 93.5 92.9 93.9 92.7 2_38_365_465 91.1 83.6 93.1 92.9 93.9 92.72_47_465_467 90.8 80.6 93.5 92.9 93.9 92.7 2_368_465_467 90.8 82.1 93.192.9 93.9 92.7 2_25_61_101 90.8 82.1 93.1 92.9 90.9 93.5 2_7_47_465 90.282.1 92.3 92.9 90.9 93.5 2_7_28_47 90.8 82.1 93.1 92.9 90.9 93.52_7_30_101 93.3 88.1 94.8 92.9 90.9 93.5 2_7_53_101 93 88.1 94.4 92.990.9 93.5 2_7_101_359 92.7 85.1 94.8 92.9 90.9 93.5 2_10_82_90 94 89.695.2 92.9 90.9 93.5 2_9_31_101 91.4 82.1 94 92.9 90.9 93.5 2_31_38_48 9385.1 95.2 92.9 84.8 95.1 2_28_31_48 93.7 86.6 95.6 92.3 87.9 93.54_7_82_101 92.4 91 92.7 92.3 93.9 91.9 4_7_38_82 91.1 85.1 92.7 92.390.9 92.7 6_7_61_68 92.1 89.6 92.7 92.3 84.8 94.3 7_25_47_466 87.3 83.688.3 92.3 87.9 93.5 7_25_48_466 89.8 85.1 91.1 92.3 84.8 94.3 4_7_82_10392.4 89.6 93.1 91.7 90.9 91.9 4_7_47_82 89.2 86.6 89.9 91.7 90.9 91.97_25_28_466 91.7 86.6 93.1 91.7 90.9 91.9 7_25_30_466 89.2 89.6 89.191.7 90.9 91.9 7_25_31_47 88.9 89.6 88.7 91.7 90.9 91.9 4_7_31_82 88.683.6 89.9 91 87.9 91.9 2_7_9_105 91.4 83.6 93.5 90.4 90.9 90.22_7_108_464 89.2 80.6 91.5 90.4 87.9 91.1 2_10_25_105 90.2 88.1 90.789.1 87.9 89.4 4_28_31_82 87.6 82.1 89.1 89.1 87.9 89.4 10_47_90_10191.1 92.5 90.7 88.5 90.9 87.8 10_30_103_365 86.3 85.1 86.7 88.5 84.889.4 9_10_61_68 90.5 86.6 91.5 88.5 78.8 91.1 10_48_68_90 93.7 89.6 94.888.5 75.8 91.9 10_30_68_365 91.1 82.1 93.5 88.5 75.8 91.9 4_7_10_82 88.986.6 89.5 87.8 84.8 88.6 4_6_10_105 81 83.6 80.2 78.8 78.8 78.9

Example 5

<Method B for Evaluating Pancreatic Cancer Discriminant Performance byCombination of Multiple Gene Markers Using Samples in the ValidationCohort>

Example 2 showed that discriminant performance was improved by using acombination of the multiple gene markers selected in Example 1, ascompared with using one of the gene marker. Thus, in this Example, eventhe gene markers that were not selected in Example 1 were studied as towhether high pancreatic cancer discriminant performance is obtained bycombinations with the gene markers selected in Example 1.

Specifically, among the genes having a gene expression level of 2⁶ orhigher in 50% or more of the samples in either of the pancreatic cancerpatient group in the training cohort or the healthy subject group in thetraining cohort, genes that showed statistical significance fordiscriminating a pancreatic cancer patient group from a healthy subjectgroup with the P value smaller than 0.5 calculated by two-tailed t-testassuming equal variance as to each gene expression level and correctedby the Bonferroni method, were examined. As a result, 161 genescontaining the 122 genes selected in Example 1 were found. Fisher'sdiscriminant analysis was conducted as to 13,042 combinations using oneor two of these 161 genes, to construct a discriminant for determiningthe presence or absence of pancreatic cancer. The discriminantperformance of the selected combinations of 1 or 2 of the genes wasvalidated in the same way as the method of Example 2.

As a result, some combinations of these genes exhibited accuracy of 85%or higher in both of the training cohort and the validation cohort andare shown in Table 12. For example, the newly found polynucleotideconsisting of the nucleotide sequence represented by SEQ ID NO: 492,493, or 494 discriminated the pancreatic cancer patients from thehealthy subjects with high discriminant performance when used incombination of two polynucleotides comprising any of the polynucleotidesconsisting of the nucleotide sequences represented by SEQ ID NOs: 1 to122. More specifically, the polynucleotide consisting of the nucleotidesequence represented by SEQ ID NO: 492, 493, or 494 was able to exhibitdiscrimination accuracy of 85% or higher between the pancreatic cancerpatients and the healthy subjects in both of the training cohort and thevalidation cohort when used in combination of two polynucleotidescomprising any of the polynucleotides consisting of the nucleotidesequences represented by SEQ ID NOs: 1, 2, 4, 7, 15, 24, 105, 107, and108. Examples of such combinations of two genes include combinations ofSEQ ID NOs: 105 and 492, SEQ ID NOs: 105 and 493, SEQ ID NOs: 1 and 492,SEQ ID NOs: 105 and 494, SEQ ID NOs: 1 and 493, SEQ ID NOs: 1 and 494,SEQ ID NOs: 107 and 493, SEQ ID NOs: 2 and 493, SEQ ID NOs: 7 and 493,SEQ ID NOs: 4 and 493, SEQ ID NOs: 2 and 492, SEQ ID NOs: 108 and 492,SEQ ID NOs: 2 and 494, SEQ ID NOs: 7 and 492, SEQ ID NOs: 7 and 494, SEQID NOs: 108 and 494, SEQ ID NOs: 4 and 492, SEQ ID NOs: 107 and 492, SEQID NOs: 107 and 494, SEQ ID NOs: 108 and 493, SEQ ID NOs: 15 and 492,SEQ ID NOs: 24 and 493, and SEQ ID NOs: 15 and 494.

As one example, an attempt was made to discriminate the pancreaticcancer patients from the healthy subjects using the expression levelmeasurement values of the nucleotide sequences represented by SEQ ID NO:105 and SEQ ID NO: 492. As a result, discriminant performance as high as97.6% accuracy, 95.5% sensitivity, and 99.0% specificity in the trainingcohort and 96.4% accuracy, 93.9% sensitivity, and 98.0% specificity inthe validation cohort was obtained.

From these results, it can be concluded that all of the polynucleotidesconsisting of the nucleotide sequences represented by SEQ ID NOs: 492 to494 are also excellent diagnostic markers.

Table 12 mentioned above is as follows.

TABLE 12 Training cohort Validation cohort Accuracy SensitivitySpecificity Accuracy Sensitivity Specificity SEQ ID NO: (%) (%) (%) (%)(%) (%) 105_492 97.6 95.5 99.0 96.4 93.9 98.0 105_493 97.6 95.5 99.096.4 93.9 98.0 1_492 97.6 97.0 98.0 94.0 90.9 96.0 105_494 96.4 94.098.0 96.4 93.9 98.0 1_493 95.8 92.5 98.0 92.8 87.9 96.0 1_494 95.8 94.097.0 92.8 87.9 96.0 107_493 94.0 88.1 98.0 89.2 84.8 92.0 2_493 92.283.6 98.0 95.2 90.9 98.0 7_493 91.0 89.6 92.0 90.4 90.9 90.0 4_493 91.085.1 95.0 88.0 87.9 88.0 2_492 90.4 79.1 98.0 96.4 93.9 98.0 108_49289.8 86.6 92.0 89.2 87.9 90.0 2_494 89.2 79.1 96.0 95.2 93.9 96.0 7_49288.6 89.6 88.0 86.7 90.9 84.0 7_494 88.6 85.1 91.0 90.4 90.9 90.0108_494 88.6 83.6 92.0 88.0 87.9 88.0 4_492 88.0 79.1 94.0 89.2 90.988.0 107_492 88.0 83.6 91.0 85.5 84.8 86.0 107_494 87.4 83.6 90.0 86.784.8 88.0 108_493 86.8 83.6 89.0 86.7 84.8 88.0 15_492 85.6 76.1 92.088.0 84.8 90.0 24_493 85.6 83.6 87.0 86.7 84.8 88.0 15_494 85.6 74.693.0 86.7 78.8 92.0

Comparative Example 1

<Pancreatic Cancer Discriminant Performance of Existing Tumor Markers inBlood>

The concentrations of the existing tumor markers CEA and CA19-9 in bloodwere measured in the training cohort and the validation cohort obtainedin the preceding Reference Examples. When the concentrations of thesetumor markers in blood are higher than the reference values described inNon-Patent Literature 3 above (CEA: 5 ng/mL, CA19-9: 37 U/mL), subjectsare usually suspected of having cancer. Thus, whether or not theconcentrations of CEA and CA19-9 in blood exceeded their referencevalues was confirmed for each sample to assess the ability of thesetumor markers to detect cancer in pancreatic cancer patients. Thesensitivity of each existing marker in the training cohort and thevalidation cohort was calculated. The results are shown in Table 5. Thesensitivity of CEA and CA19-9 was as low as 55.2% and 77.6%,respectively, in the training cohort, and was as low as 45.5% and 75.8%,respectively, in the validation cohort, demonstrating that neither ofthe markers are useful in the detection of pancreatic cancer (Table 5).

On the other hand, as shown above in Tables 3 and 6 of Examples 1 and 2,it can be concluded that in all of the polynucleotides consisting of thenucleotide sequences represented by SEQ ID NOs: 1 to 122, combinationsof 1, 2 or more polynucleotides exhibiting sensitivity beyond theexisting pancreatic cancer markers are present, and thus suchpolynucleotides serve as excellent diagnosis markers.

As shown in these Examples and Comparative Example, the kit and themethod of the present invention can detect pancreatic cancer with highersensitivity than the existing tumor markers and therefore permit earlydecision to carry out the surgical resection of a cancer site. As aresult, improvement in 5-year survival rate and reduction in the rate ofrecurrence can be achieved.

INDUSTRIAL APPLICABILITY

According to the present invention, pancreatic cancer can be effectivelydetected by a simple and inexpensive method. This enables earlydetection, diagnosis and treatment of pancreatic cancer. The method ofthe present invention can detect pancreatic cancer with limitedinvasiveness using the blood of a patient and therefore allowspancreatic cancer to be detected conveniently and rapidly.

All publications, patents, and patent applications cited herein areincorporated herein by reference in their entirety.

SEQUENCE LISTING

The invention claimed is:
 1. A method for detecting pancreatic cancer,comprising: measuring an expression level of hsa-miR-4294 in a samplecomprising blood, serum, or plasma from a human subject using a kitcomprising a nucleic acid(s), as a primer(s) or a probe(s), capable ofspecifically binding to hsa-miR-4294, wherein the measuring comprisesthe following steps of: (a) contacting hsa-miR-4294 in the sample orcomplementary polynucleotide(s) thereof prepared from hsa-miR-4294 withthe nucleic acid(s); (b) measuring an expression level of hsa-miR-4294using the nucleic acid(s) as the primer(s), or using the nucleic acidsas the probe(s); and (c) comparing the expression level of hsa-miR-4294measured in the step (b) with a control expression level of hsa-miR-4294in a control sample from a healthy subject measured in the same way asin the step (b), wherein a lower expression level of hsa-miR-4294 in thesample comprising blood, serum, or plasma from the subject as comparedto the control expression level is detected and is indicative that thesubject has pancreatic cancer; and treating the subject for pancreaticcancer or performing a diagnostic procedure on the subject, wherein thetreatment comprises surgery, radiotherapy, chemotherapy or a combinationthereof, and wherein the diagnostic procedure comprises abdominalultrasonography, CT scanning, endoscopic retrogradecholangiopancreatography, or endoscopic ultrasonography, or acombination thereof.
 2. A method for detecting pancreatic cancer,comprising: measuring an expression level of hsa-miR-4294 in a samplecomprising blood, serum, or plasma from a human subject using a devicecomprising a nucleic acid(s), as a probe(s), capable of specificallybinding to hsa-miR-4294, wherein the measuring comprises the followingsteps of: (a) binding hsa-miR-4294 in the sample or cDNA thereofprepared from hsa-miR-4294 to the nucleic acid(s) to measure anexpression level of hsa-miR-4294 by hybridization using the nucleicacid(s); and (b) comparing the expression level of hsa-miR-4294 measuredin the step (a) with a control expression level of hsa-miR-4294 in acontrol sample from a healthy subject measured in the same way as in thestep (a), wherein a lower expression level of hsa-miR-4294 in the samplecomprising blood, serum, or plasma from the subject as compared to thecontrol expression level is detected and is indicative that the subjecthas pancreatic cancer; and treating the subject for pancreatic cancer orperforming a diagnostic procedure on the subject, wherein the treatmentcomprises surgery, radiotherapy, chemotherapy or a combination thereof,and wherein the diagnostic procedure comprises abdominalultrasonography, CT scanning, endoscopic retrogradecholangiopancreatography, or endoscopic ultrasonography, or acombination thereof.
 3. The method according to claim 1, wherein thestep (c) further comprises preparing a discriminant based on a setformula to determine whether or not the subject has pancreatic cancer.4. The method according to claim 2, wherein the step (b) furthercomprises preparing a discriminant based on a set formula to determinewhether or not the human subject has pancreatic cancer.
 5. The methodaccording to claim 3, wherein the discriminant is compared to a setthreshold to determine whether or not the subject has pancreatic cancer.6. The method according to claim 4, wherein the discriminant is comparedto a set threshold to determine whether or not the subject haspancreatic cancer.
 7. The method according to claim 1, wherein the kitfurther comprises one or more nucleic acids, as a primer(s) or aprobe(s), capable of specifically binding to one or more other humanpancreatic cancer markers selected from the group consisting of:miR-6893-5p, miR-6075, miR-6820-5p, miR-6729-5p, miR-4476, miR-6836-3p,miR-6765-3p, miR-6799-5p, miR-4530, miR-7641, miR-4454, miR-615-5p,miR-8073, miR-663a, miR-4634, miR-4450, miR-4792, miR-665, miR-7975,miR-7109-5p, miR-6789-5p, miR-4497, miR-6877-5p, miR-6880-5p, miR-7977,miR-4734, miR-6821-5p, miR-8089, miR-5585-3p, miR-6085, miR-6845-5p,miR-4651, miR-4433-3p, miR-1231, miR-4665-5p, miR-7114-5p, miR-1238-5p,miR-8069, miR-4732-5p, miR-619-5p, miR-3622a-5p, miR-1260a, miR-6741-5p,miR-6781-5p, miR-6125, miR-6805-5p, miR-6132, miR-6872-3p, miR-6875-5p,miR-1908-3p, miR-4433b-3p, miR-4736, miR-5100, miR-6724-5p, miR-7107-5p,miR-6726-5p, miR-3185, miR-4638-5p, miR-1273g-3p, miR-6778-5p,miR-328-5p, miR-3679-3p, miR-1228-3p, miR-6779-5p, miR-4723-5p,miR-6850-5p, miR-760, miR-7704, miR-8072, miR-4486, miR-1913, miR-4656,miR-1260b, miR-7106-5p, miR-6889-5p, miR-6780b-5p, miR-6090, miR-4534,miR-4449, miR-5195-3p, miR-1202, miR-4467, miR-6515-3p, miR-4281,miR-4505, miR-4484, miR-6805-3p, miR-3135b, miR-3162-5p, miR-6768-5p,miR-6721-5p, miR-1227-5p, miR-6722-3p, miR-4286, miR-4746-3p,miR-6727-5p, miR-6816-5p, miR-4741, miR-4508, miR-940, miR-4327,miR-4665-3p, miR-718, miR-1203, miR-663b, miR-4258, miR-4649-5p,miR-4516, miR-3619-3p, miR-6826-5p, miR-6757-5p, miR-3131, miR-1343-3p,miR-6775-5p, miR-6813-5p, and miR-3940-5p, and/or, miR-125a-3p,miR-204-3p, miR-1469, miR-575, miR-150-3p, miR-423-5p, miR-564,miR-3188, miR-1246, miR-602, miR-1290, miR-16-5p, miR-451a, miR-24-3p,miR-187-5p, miR-1908-5p, miR-371a-5p, miR-550a-5p, miR-4417,miR-4707-5p, miR-7847-3p, miR-2861, miR-4513, miR-7111-5p, miR-6777-5p,miR-7113-3p, miR-4648, miR-3184-5p, miR-4271, miR-6791-5p, miR-642a-3p,miR-7108-5p, miR-128-1-5p, miR-5196-5p, miR-3178, miR-3656,miR-92a-2-5p, miR-6769b-5p, miR-4689, miR-6076, miR-92b-5p, miR-6774-5p,miR-486-3p, miR-6806-5p, miR-6842-5p, miR-6716-5p, miR-557, miR-4673,miR-4674, miR-4442, miR-1915-3p, miR-4687-3p, and miR-92b-3p, and themethod further comprises: measuring expression levels of the one or moreother human pancreatic cancer markers in the sample by the same way asin the steps (a), (b) and (c) using the nucleic acid(s); and evaluatingin vitro whether or not the subject has pancreatic cancer on the basisof lower or higher expression levels indicated in Table 7, incombination with the measured expression level of hsa-miR-4294, bycomparing to control expression levels from healthy subjects.
 8. Themethod according to claim 2, wherein the device further comprises one ormore nucleic acids, as a probe(s), capable of specifically binding toone or more other human pancreatic cancer markers selected from thegroup consisting of: miR-6893-5p, miR-6075, miR-6820-5p, miR-6729-5p,miR-4476, miR-6836-3p, miR-6765-3p, miR-6799-5p, miR-4530, miR-7641,miR-4454, miR-615-5p, miR-8073, miR-663a, miR-4634, miR-4450, miR-4792,miR-665, miR-7975, miR-7109-5p, miR-6789-5p, miR-4497, miR-6877-5p,miR-6880-5p, miR-7977, miR-4734, miR-6821-5p, miR-8089, miR-5585-3p,miR-6085, miR-6845-5p, miR-4651, miR-4433-3p, miR-1231, miR-4665-5p,miR-7114-5p, miR-1238-5p, miR-8069, miR-4732-5p, miR-619-5p,miR-3622a-5p, miR-1260a, miR-6741-5p, miR-6781-5p, miR-6125,miR-6805-5p, miR-6132, miR-6872-3p, miR-6875-5p, miR-1908-3p,miR-4433b-3p, miR-4736, miR-5100, miR-6724-5p, miR-7107-5p, miR-6726-5p,miR-3185, miR-4638-5p, miR-1273g-3p, miR-6778-5p, miR-328-5p,miR-3679-3p, miR-1228-3p, miR-6779-5p, miR-4723-5p, miR-6850-5p,miR-760, miR-7704, miR-8072, miR-4486, miR-1913, miR-4656, miR-1260b,miR-7106-5p, miR-6889-5p, miR-6780b-5p, miR-6090, miR-4534, miR-4449,miR-5195-3p, miR-1202, miR-4467, miR-6515-3p, miR-4281, miR-4505,miR-4484, miR-6805-3p, miR-3135b, miR-3162-5p, miR-6768-5p, miR-6721-5p,miR-1227-5p, miR-6722-3p, miR-4286, miR-4746-3p, miR-6727-5p,miR-6816-5p, miR-4741, miR-4508, miR-940, miR-4327, miR-4665-3p,miR-718, miR-1203, miR-663b, miR-4258, miR-4649-5p, miR-4516,miR-3619-3p, miR-6826-5p, miR-6757-5p, miR-3131, miR-1343-3p,miR-6775-5p, miR-6813-5p, and miR-3940-5p, and/or, miR-125a-3p,miR-204-3p, miR-1469, miR-575, miR-150-3p, miR-423-5p, miR-564,miR-3188, miR-1246, miR-602, miR-1290, miR-16-5p, miR-451a, miR-24-3p,miR-187-5p, miR-1908-5p, miR-371a-5p, miR-550a-5p, miR-4417,miR-4707-5p, miR-7847-3p, miR-2861, miR-4513, miR-7111-5p, miR-6777-5p,miR-7113-3p, miR-4648, miR-3184-5p, miR-4271, miR-6791-5p, miR-642a-3p,miR-7108-5p, miR-128-1-5p, miR-5196-5p, miR-3178, miR-3656,miR-92a-2-5p, miR-6769b-5p, miR-4689, miR-6076, miR-92b-5p, miR-6774-5p,miR-486-3p, miR-6806-5p, miR-6842-5p, miR-6716-5p, miR-557, miR-4673,miR-4674, miR-4442, miR-1915-3p, miR-4687-3p, and miR-92b-3p, and themethod further comprises: measuring expression levels of the one or moreother human pancreatic cancer markers in the sample by the same way asin the steps (a) and (b) using the nucleic acid(s); and evaluating invitro whether or not the subject has pancreatic cancer on the basis oflower or higher expression levels indicated in Table 7, in combinationwith the measured expression level of hsa-miR-4294, by comparing tocontrol expression levels from healthy subjects.
 9. The method accordingto claim 7, wherein the step (c) further comprises preparing adiscriminant based on a set formula to determine whether or not thesubject has pancreatic cancer.
 10. The method according to claim 8,wherein the step (b) further comprises preparing a discriminant based ona set formula to determine whether or not the human subject haspancreatic cancer.
 11. The method according to claim 9, wherein thediscriminant is compared to a set threshold to determine whether or notthe subject has pancreatic cancer.
 12. The method according to claim 10,wherein the discriminant is compared to a set threshold to determinewhether or not the subject has pancreatic cancer.